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Glycyrrhizin (GL) has immunoregulatory effects on various inflammatory diseases including hepatitis and nephritis. However, the mechanisms underlying the anti-inflammatory effect of GL on renal inflammation are not fully understood. Hepatorenal syndrome (HRS) is a functional acute renal impairment that occurs in severe liver disease, and we found that kidney injury also occurs in Con A-induced experimental hepatitis in mice. We previously found that GL can alleviate Con A-induced hepatitis by regulating the expression of IL-25 in the liver. We wanted to investigate whether GL can alleviate Con A-induced nephritis by regulating IL-25. IL-25 regulates inflammation by modulating type 2 immune responses, but the mechanism by which IL-25 affects kidney disease remains unclear. In this study, we found that the administration of GL enhanced the expression of IL-25 in renal tissues; the latter promoted the generation of type 2 macrophages (M2), which inhibited inflammation in the kidney caused by Con A challenge. IL-25 promoted the secretion of the inhibitory cytokine IL-10 by macrophages but inhibited the expression of the inflammatory cytokine IL-1β by macrophages. Moreover, IL-25 downregulated the Con A-mediated expression of Toll-like receptor (TLR) 4 on macrophages. By comparing the roles of TLR2 and TLR4, we found that TLR4 is required for the immunoregulatory effect of IL-25 on macrophages. Our data revealed that GL has anti-inflammatory effects on Con A-induced kidney injury and that the GL/IL-25/M2 axis participates in the anti-inflammatory process. This study suggested that GL is a potential therapeutic for protecting against acute kidney injury.

Introduction: Vitexin is a natural flavonoid compound extracted from Vitex leaves or seeds, exhibiting various pharmacological activities including anticancer, antihypertensive, anti-inflammatory, and spasmolytic effects. However, its protective effects on hypertensive nephropathy (HN) and the underlying mechanisms remain unclear., Methods: Spontaneous hypertension rats were fed a high-sugar and high-fat diet for 8 weeks to induce the disease HN model. From the 5th week, the rats were administered vitexin via gavage. Blood pressure was measured biweekly using the tail-cuff method. Histopathological changes were assessed using HE staining, and biochemical analyses were performed to evaluate the effects of vitexin on HN rats. The underlying mechanisms of vitexin treatment were investigated through western blotting., Results: The data demonstrated that vitexin significantly lowered systolic, diastolic, and mean arterial pressures and ameliorated histopathological changes in HN rats. Biochemical analyses revealed that vitexin reduced the levels of creatinine (Cr), blood urea nitrogen (BUN), total cholesterol (TC), triglycerides (TG), total protein (TP), low-density lipoprotein cholesterol (LDL-C), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), and advanced glycation end products (AGEs), while increasing the levels of albumin (ALB) and superoxide dismutase (SOD). Western blotting results indicated that vitexin treatment decreased the expression of TNF-α, IL-6, and nuclear factor kappa-B (NF-κB), while increasing the expression of SOD., Conclusion: The findings of this study suggest that vitexin exerts protective effects against HN, providing pharmacological evidence for its potential use in HN treatment., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Abstract: Catalpol is an iridoid glycoside obtained from Rehmannia glutinosa, which in previous studies showed various pharmacological properties, including anti-inflammatory, antioxidant, antidiabetic, antitumor, and dopaminergic neurons protecting effects. Here, we examined the effect of catalpol on renal injury induced by angiotensin II (Ang II) and further to explore its latent molecular mechanisms. We used an in vivo model of Ang II-induced renal injury mice; catalpol (25, 50, and 100 mg/kg) was administered for 28 days. Mouse glomerular mesangial cells (SV40 MES 13), rat kidney interstitial fibroblasts cells (NRK-49F), and human proximal tubular epithelial cells (HK-2) were induced by Ang II (10 µM) in the presence or absence of catalpol (1, 5, and 10 µM) and incubated for 48 hours in vitro. In our study, periodic acid-Schiff and Masson staining of renal tissue showed that catalpol reduced Ang II-induced renal injury in a concentration-dependent manner. The positive expressions of collagen IV and TGF-β1 were observed to decrease sharply after catalpol treatment. In renal tissue, the levels of pro-inflammatory cytokines tumor necrosis factor α and interleukin 6 were evidently decreased after catalpol intervention. Catalpol can relieve Ang II-induced renal injury by inactivating NF-κB and TGF-β1/Smads signaling pathways. Therefore, catalpol may act as a potential drug to treat Ang II-induced renal injury., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

15-Lipoxygenase (15-LO) is a nonheme iron-containing dioxygenase that has both pro- and anti-inflammatory roles in many tissues and disease states. 15-LO is thought to influence macrophage phenotype, and silencing 15-LO reduces fibrosis after acute inflammatory triggers. The goal of the present study was to determine whether altering 15-LO expression influences inflammation and fibrogenesis in a murine model of unilateral ureteral obstruction (UUO). C57BL/6J mice, 15-LO knockout ( Alox15 -/- ) mice, and 15-LO transgenic overexpressing (15LOTG) mice were subjected UUO, and kidneys were analyzed at 3, 10, and 14 days postinjury. Histology for fibrosis, inflammation, cytokine quantification, flow cytometry, and metabolomics were performed on injured tissues and controls. PD146176, a specific 15-LO inhibitor, was used to complement experiments involving knockout animals. Compared with wild-type animals undergoing UUO, Alox15 -/- mouse kidneys had less proinflammatory, profibrotic message along with less fibrosis and macrophage infiltration. PD146176 inhibited 15-LO and resulted in reduced fibrosis and macrophage infiltration similar to Alox15 -/- mice. Flow cytometry revealed that Alox15 -/- UUO-injured kidneys had a dynamic change in macrophage phenotype, with an early blunting of CD11b Hi Ly6C Hi "M1" macrophages and an increase in anti-inflammatory CD11b Hi Ly6C Int "M2c" macrophages and reduced expression of the fractalkine receptor chemokine (C-X3-C motif) receptor 1. Many of these findings were reversed when UUO was performed on 15LOTG mice. Metabolomics analysis revealed that wild-type kidneys developed a glycolytic shift postinjury, while Alox15 -/- kidneys exhibited increased oxidative phosphorylation. In conclusion, 15-LO manipulation by genetic or pharmacological means induces dynamic changes in the inflammatory microenvironment in the UUO model and appears to be critical in the progression of UUO-induced fibrosis. NEW & NOTEWORTHY 15-Lipoxygenase (15-LO) has both pro- and anti-inflammatory functions in leukocytes, and its role in kidney injury and repair is unexplored. Our study showed that 15-LO worsens inflammation and fibrosis in a rodent model of chronic kidney disease using genetic and pharmacological manipulation. Silencing 15-LO promotes an increase in M2c-like wound-healing macrophages in the kidney and alters kidney metabolism globally, protecting against anaerobic glycolysis after injury.

Acute kidney injury (AKI) is one of the most common diseases in patients treated in intensive care units. This study was intended to explore the underlying mechanism by which ulinastatin (UTI) influenced the inflammation and apoptosis of renal tubular epithelial cells, HK-2.The effects of UTI on the cell viability of HK-2 cells were first measured by MTT and lactate dehydrogenase (LDH) detection kit. The apoptosis and inflammation of HK-2 cells were then determined by TUNEL, western blot, ELISA, and RT-qPCR. Then, the proteins in the Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme oxygenase 1 (HO-1) signaling pathways were measured by western blot for confirming the relationship between UTI and these pathways. Finally, Nrf-2 inhibitor ML385 and TLR4 activator CCL-34 were respectively used on LPS-induced HK-2 cells exposed to UTI for the conduction of gain-of-function and loss-of-function assays.UTI treatment boosted the cell viability of HK-2 cells damaged by LPS. Furthermore, UTI exposure cut down the apoptosis rate and inhibited the expression inflammatory factors of HK-2 cells induced by LPS. UTI treatment decreased the expression of proteins in the TLR4/NF-κB pathway, increased the HO-1 expression, and prompted the translocation of Nrf2 from the cytoplasm to the nucleus. The alleviated effects of UTI on inflammation and apoptosis LPS-induced HK-2 cells were abolished by ML385 and TLR4, respectively.UTI attenuates LPS-induced inflammation and inhibits endoplasmic reticulum stress-induced apoptosis in renal tubular epithelial cells by regulating TLR4/NF-κB and Nrf2/HO-1 pathways., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Studies have shown that ursolic acid (UA) and empagliflozin (EM) exert therapeutic effects in the treatment of diabetic nephropathy (DN), but both drugs have disadvantages. This study explores the effect of combining these drugs compared to that of either monotherapy. A diabetic rat model was established by feeding a high-fat diet (HFD) with high-sugar content and administering a low dose of streptozotocin (STZ) via intraperitoneal injection. UA (50 mg/kg/day, po), EM (10 mg/kg/day, po) or both were administered for 8 weeks. The development of DN was determined by observing increases in urine protein, serum creatinine, urea nitrogen, and uric acid and abnormal changes in kidney morphology. UA and EM either alone or in combination can alleviate the increases in blood glucose, glycosylated haemoglobin, blood lipid levels, inflammatory factors (TNF-α, IL-1β, IL-6), oxidation factors (SOD, MDA, GSH, CAT, NO), renal fibrosis and pro-fibrosis factors (FN, E-cad, MMP-9, TIMP-1, SMA-α, TGF-β1, SMAD, MAPK). The treatments could also ameliorate DN by preventing the abnormal proliferation of glomerular mesangial cells under high-glucose conditions, aberrant apoptosis and excessive production of reactive oxygen species (ROS). In addition, UA reduces the increase in LDL-L, reverses abnormal bladder morphology and mitigates the increase in colony count caused by EM, and the combination treatment can overcome the disadvantages of the slow hypoglycaemic effect of UA. In short, UA combined with empagliflozin is more effective than either monotherapy in the treatment of DN and can cancel the adverse effects of each other. The protective effect of this regimen on the kidney may be related to reducing inflammation, oxidative stress and renal fibrosis., (Copyright © 2021. Published by Elsevier Masson SAS.)

Opuntia dillenii is a medicinal plant with frequent usage in folk medicine to treat many illnesses. The present study aims to investigate the protective effect of Opuntia dillenii seed oil against gentamicin-induced nephrotoxicity in rats. The animals (rats) were randomly divided into three groups (i) the normal control group treated only with distilled water (10 mL/kg), (ii) the gentamicin group treated with distilled water (10 mL/kg) and received an intraperitoneal injection of gentamicin (80 mg/kg), and (iii) the group treated with the Opuntia dillenii seed oil (2 mL/kg) and also received an intraperitoneal injection of gentamicin (80 mg/kg). The rats received their following treatments for 14 consecutive days orally. Serum urea, creatinine, gamma-glutamyl transferase, albumin, and electrolyte levels were quantified as the markers of acute renal and liver failure. Besides, the kidney and liver relative weight, kidney malondialdehydes, and kidney histological analysis were determined. The results have shown that daily pretreatment with Opuntia dillenii seed oil (2 mL/kg) prevented severe alterations of biochemical parameters and disruptions of kidney tissue structures. In addition, the results of the present study showed for the first time that Opuntia dillenii seed oil reduced renal toxicity in gentamicin-induced nephrotoxicity in rats. Therefore, Opuntia dillenii seed oil may represent a new therapeutic avenue to preserve and protect renal function in gentamicin-treated patients., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2021 Mohamed Bouhrim et al.)

Diabetic nephropathy (DN) is a chronic inflammatory renal disease induced by hyperglycemia. Recent studies have implicated cyclin-dependent kinase 9 (CDK9) in inflammatory responses and renal fibrosis. In this study, we explored a potential role of CDK9 in DN by using cultured mouse mesangial cell line SV40 MES-13 and streptozotocin-induced type 1 mouse model of diabetes. We inhibited CDK9 in mice and in cultured cells by a highly selective CDK9 inhibitor, LDC000067 (LDC), and evaluated inflammatory and fibrogenic outcome by mRNA and protein analyses. Our studies show that treatment of diabetic mice with LDC significantly inhibits the levels of inflammatory cytokines and fibrogenic genes in kidney specimens. These reductions were associated with improved renal function. We also found that LDC treatment suppressed MAPK-AP1 activation. We then confirmed the involvement of CDK9 in cultured SV40 MES-13 cells and showed that deficiency in CDK9 prevents glucose-induced inflammatory and fibrogenic proteins. This protection was also afforded by suppression of MAPK-AP1. Taken together, our results how that hyperglycemia activates CDK9-MAPK-AP1 axis in kidneys to induce inflammation and fibrosis, leading to renal dysfunction. Our findings also suggest that CDK9 may serve as a potential therapeutic target for DN., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) is a frequent complication of sepsis and an important cause of morbidity and mortality worldwide. A cornerstone of sepsis-associated AKI is dysregulated inflammation, leading to increased tissue oxidative stress and free radical formation, which leads to multiple forms of cell death. DJ-1 is a peroxiredoxin protein with multiple functions, including its ability to control cellular oxidative stress. Although DJ-1 is expressed prominently by renal tubules, its role in AKI has not been investigated. In the present study, we examined the effect of DJ-1 deficiency in a murine model of endotoxin-induced AKI. Endotoxemia induced greater kidney injury in DJ-1-deficient mice. Furthermore, DJ-1 deficiency increased renal oxidative stress associated with increased renal tubular apoptosis and with expression of death domain-associated protein (DAXX). Similar to the in vivo model, in vitro experiments using a medullary collecting duct cell line (mIMCD3) and cytotoxic serum showed that serum obtained from wild-type mice resulted in increased expression of s100A8/s100A9, DAXX, and apoptosis in DJ-1-deficient mIMCD3 cells. Our findings demonstrate a novel renal protective role for renal tubular DJ-1 during endotoxemia through control of oxidative stress, renal inflammation, and DAXX-dependent apoptosis.

Background: Chronic kidney disease of non-traditional origin (CKDnt) is common among Mesoamerican sugarcane workers. Recurrent heat stress and dehydration is a leading hypothesis. Evidence indicate a key role of inflammation., Methods: Starting in sports and heat pathophysiology literature, we develop a theoretical framework of how strenuous work in heat could induce kidney inflammation. We describe the release of pro-inflammatory substances from a leaky gut and/or injured muscle, alone or in combination with tubular fructose and uric acid, aggravation by reduced renal blood flow and increased tubular metabolic demands. Then, we analyze longitudinal data from >800 sugarcane cutters followed across harvest and review the CKDnt literature to assess empirical support of the theoretical framework., Results: Inflammation (CRP elevation and fever) and hyperuricemia was tightly linked to kidney injury. Rehydrating with sugary liquids and NSAID intake increased the risk of kidney injury, whereas electrolyte solution consumption was protective. Hypokalemia and hypomagnesemia were associated with kidney injury., Discussion: Heat stress, muscle injury, reduced renal blood flow and fructose metabolism may induce kidney inflammation, the successful resolution of which may be impaired by daily repeating pro-inflammatory triggers. We outline further descriptive, experimental and intervention studies addressing the factors identified in this study.

Renal ischemia-reperfusion (IR) injury is one of the most common acute kidney injuries, but there is still a lack of effective treatment in the clinical setting. Trehalose (Tre), a natural disaccharide, has been demonstrated to protect against oxidative stress, inflammation, and apoptosis. However, whether it could protect against IR-induced renal injury needs to be investigated. In an in vivo experiment, C57BL/6J mice were pretreated with or without Tre (2 g/kg) through a daily single intraperitoneal injection from 3 days before renal IR surgery. Renal function, apoptosis, oxidative stress, and inflammation were analyzed to evaluate kidney injury. In an in vitro experiment, mouse proximal tubular cells were treated with or without Tre under a hypoxia/reoxygenation condition. Western blot analysis, autophagy flux detection, and apoptosis assay were performed to evaluate the level of autophagy and antiapoptotic effect of Tre. The in vivo results showed that the renal damage induced by IR was ameliorated by Tre treatment, as renal histology and renal function were improved and the enhanced protein levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were blocked. Moreover, autophagy was activated by Tre pretreatment along with inhibition of the IR injury-induced apoptosis, oxidative stress, and inflammation. The in vitro results showed that Tre treatment activated autophagy and protected against hypoxia/reoxygenation-induced tubular cell apoptosis and oxidative stress. Our results demonstrated that Tre protects against IR-induced renal injury, possibly by enhancing autophagy and blocking oxidative stress, inflammation, and apoptosis, suggesting its potential use for the clinical treatment of renal IR injury.

Background: Increased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α 2A-adrenoceptors on sympathetic nerves, and α 2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α 2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown., Methods: We investigated effects of α 2A-adrenoceptor-regulated renal NE release on the development of angiotensin II-dependent hypertension and kidney disease. In uninephrectomized wild-type and α 2A-adrenoceptor-knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days., Results: Urinary NE excretion and BP did not differ between normotensive α 2A-adrenoceptor-knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α 2A-adrenoceptor-knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α 2A-adrenoceptor-knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α 2A-adrenoceptor-deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α 2A-adrenoceptor-knockout mice after renal denervation., Conclusions: Our findings reveal a protective role of prejunctional inhibitory α 2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment., (Copyright © 2020 by the American Society of Nephrology.)

Background The cardiovascular protective effects of estrogens in premenopausal women depend mainly on estrogen receptor α (ERα). ERα activates nuclear gene transcription regulation and membrane-initiated signaling. The latter plays a key role in estrogen-dependent activation of endothelial NO synthase. The goal of the present work was to determine the respective roles of the 2 ERα activities in endothelial function and cardiac and kidney damage in young and old female mice with hypertension, which is a major risk factor in postmenopausal women. Methods and Results Five- and 18-month-old female mice lacking either ERα (ERα -/- ), the nuclear activating function AF2 of ERα (AF2°), or membrane-located ERα (C451A) were treated with angiotensin II (0.5 mg/kg per day) for 1 month. Systolic blood pressure, left ventricle weight, vascular reactivity, and kidney function were then assessed. Angiotensin II increased systolic blood pressure, ventricle weight, and vascular contractility in ERα -/- and AF2° mice more than in wild-type and C451A mice, independent of age. In both the aorta and mesenteric resistance arteries, angiotensin II and aging reduced endothelium-dependent relaxation in all groups, but this effect was more pronounced in ERα -/- and AF2° than in the wild-type and C451A mice. Kidney inflammation and oxidative stress, as well as blood urea and creatinine levels, were also more pronounced in old hypertensive ERα -/- and AF2° than in old hypertensive wild-type and C451A mice. Conclusions The nuclear ERα-AF2 dependent function attenuates angiotensin II-dependent hypertension and protects target organs in aging mice, whereas membrane ERα signaling does not seem to play a role.

Glucagon-like peptide (GLP)-1 analogs such as liraglutide improved albuminuria in patients with type 2 diabetes in large randomized controlled trials. One of the suspected mechanisms is the anti-inflammatory potential of GLP-1 receptor (Glp1r) agonism. Thus, the anti-inflammatory action of Glp1r agonism was tested in a nondiabetic, T-cell-mediated murine model of nephrotoxic serum nephritis (NTS). The role of Glp1r in NTS was evaluated by using Glp1r -/- mice or C57BL/6 mice treated with liraglutide. In vitro, murine T cells were stimulated in the presence of liraglutide or vehicle. Glp1r -/- mice displayed increased renal infiltration of neutrophils and T cells after induction of NTS. Splenocyte proliferation and TH1 cytokine transcription were increased in spleen and lymph nodes of Glp1r -/- mice. Liraglutide treatment significantly improved the renal outcome of NTS in C57BL/6 mice by decreasing renal infiltration and proliferation of T cells, which resulted in decreased macrophage infiltration. In vitro, T cells stimulated in the presence of liraglutide showed decreased proliferation of TH1 and TH17 cells. Liraglutide blocked glycolysis in T cells and decreased their Glut1 mRNA expression. Together, Glp1r agonism protects mice from a T-cell-dependent glomerulonephritis model by inhibition of T-cell proliferation, possibly by interacting with their metabolic program. This mechanism may explain in part the renoprotective effects of Glp1r agonism in diabetic nephropathy., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background Oxidative stress and high salt intake could be independent or intertwined risk factors in the origin of hypertension. Kidneys are the major organ to regulate sodium homeostasis and blood pressure and the renal dopamine system plays a pivotal role in sodium regulation during sodium replete conditions. Oxidative stress has been implicated in renal dopamine dysfunction and development of hypertension, especially in salt-sensitive animal models. Here we show the nexus between high salt intake and oxidative stress causing renal tubular dopamine oxidation, which leads to mitochondrial and lysosomal dysfunction and subsequently causes renal inflammation and hypertension. Methods and Results Male Sprague Dawley rats were divided into the following groups, vehicle (V)-tap water, high salt (HS)-1% NaCl, L-buthionine-sulfoximine (BSO), a prooxidant, and HS plus BSO without and with antioxidant resveratrol (R) for 6 weeks. Oxidative stress was significantly higher in BSO and HS+BSO-treated rat compared with vehicle; however, blood pressure was markedly higher in the HS+BSO group whereas an increase in blood pressure in the BSO group was modest. HS+BSO-treated rats had significant renal dopamine oxidation, lysosomal and mitochondrial dysfunction, and increased renal inflammation; however, HS alone had no impact on organelle function or inflammation. Resveratrol prevented oxidative stress, dopamine oxidation, organelle dysfunction, inflammation, and hypertension in BSO and HS+BSO rats. Conclusions These data suggest that dopamine oxidation, especially during increased sodium intake and oxidative milieu, leads to lysosomal and mitochondrial dysfunction and renal inflammation with subsequent increase in blood pressure. Resveratrol, while preventing oxidative stress, protects renal function and mitigates hypertension.

Henoch-Schönlein purpura (HSP) is regarded as a benign and self-limiting vasculitis characterized by purpura, arthritis, and gastrointestinal symptoms; however, about one third of the patients develop HSP nephritis (HSPN), the most serious long-term complication. Since 2013, we have proposed that tonsillectomy in addition to intravenous methylprednisolone pulse therapy (IVMP) be performed in all patients with HSPN, similar to immunoglobulin A nephropathy (IgAN) patients because both diseases are considered to a share common pathogenesis. Herein, we retrospectively reviewed the clinical courses of 71 Japanese children with HSPN (34 boys; median age at diagnosis, 6.7 years; median follow-up period, 5.6 years) who had received initial treatment with IVMP (15-20 mg/kg; on 3 consecutive days/week for 3 weeks) followed by oral prednisolone (initially 1 mg/kg; tapered off within 12 months) and achieved clinical remission (i.e., disappearance of both proteinuria and hematuria). The patients were divided into two groups: 31 patients receiving tonsillectomy after IVMP between 2013 and 2017 (tonsillectomy group) and 40 patients receiving IVMP monotherapy between 2003 and 2012 (IVMP group). For the 2 years after IVMP therapy, the rate of HSPN recurrence (i.e., persistent proteinuria combined with hematuria requiring additional treatments) after clinical remission was significantly lower in the tonsillectomy group than the IVMP group (0% vs. 19%, P < 0.05). Despite the short follow-up period in the tonsillectomy group, this study provides the evidence that tonsillectomy may be beneficial for preventing recurrence of HSPN from clinical remission with IVMP therapy in Japanese children.

Background and Aims: P-Coumaric acid (PCA) is one the compound that has free radical scavenging effects. This study investigates the protective effect of PCA on tissue damage in DOX-induced nephrotoxicity., Methods: Thirty two Wistar rats were divided into control, PCA, DOX (15 mg/kg, i.p.) and DOX plus PCA (100 mg/kg, orally) groups. DOX-induced nephrotoxicity was indicated by marked increase in blood urea nitrogen (BUN) and serum creatinine (Cr) compared to controls. DOX group also showed elevations in lipid peroxidation and reductions in enzyme activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT). Expression of renal inflammatory cytokines including tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) and apoptosis were also elevated in the DOX group., Results: PCA significantly reversed, nephrotoxicity induced by DOX via lowering BUN, serum Cr and improving histopathological scores as compared to the DOX group. PCA also decreased lipid peroxidation, increased activities of GPx, SOD and CAT, to levels relatively comparable to control. Significant reductions in expression of TNF-α, IL-1β and apoptosis were also observed following Co-administration of PCA relative to the DOX group., Conclusions: Results describe a protective effect of PCA against DOX-induced nephrotoxicity. This effect is likely facilitated through inhibition of oxidative stress, inflammation and apoptosis., (Copyright © 2019 IMSS. Published by Elsevier Inc. All rights reserved.)

Previous study found that the fruit body of Irpex lacteus has an effect on the prevention and treatment of chronic nephritis. In this study, we systematically investigated the preventive effect of small molecular fraction (SMF) of the fungal fruit body against chronic nephritis. In addition, we analyzed, isolated, and identified the chemical constituents of SMF, and screened the activity of three small peptides isolated in vitro. The results showed SMF significantly reduced amounts of urine protein (UP), the content of urea (BUN), creatinine (Cr), tumor necrosis factor-α (TNF-α), and maleic dialdehyde (MDA) in serum, and significantly increased superoxide dismutase (SOD) level in renal tissue homogenate (P < 0.05). Moreover, the results of hematoxylin and eosin (H&E) and Masson staining of renal tissues indicated that SMF has protective effects on renal tissues and prevents renal interstitial from fibrosis. The peptide sequences isolated from SMF were identified as WSMGPAPDSVH (SP1), QCTGNASCSPPC (SP2), and HYCCTAKYA (SP3), which were active compounds for the prevention of nephritis, and these new peptides were isolated for the first time. The cell proliferation assay showed that 10 μg/L transforming growth factor-β1 (TGF-β1) significantly induced the proliferation of human renal tubular epithelial cells (HK-2), compared with the control group, and the difference was statistically significant (P < 0.01). However, when combined with three small peptides, respectively, the cell proliferation was significantly inhibited (P < 0.05). These results suggest that isolated peptides can maintain the morphological stability of HK-2 cells, inhibit cell proliferation induced by TGF-β1 to some extent, and prevent cell fibrosis.

To simulate clinical features in human chronic kidney disease (CKD), SD rats were subjected to 5/6 nephrectomy in this study. We found that periostin gene was upregulated in the remnant kidneys using Agilent gene microarrays, and further explored its role via in vivo and in vitro experiments. Intrarenal renin-angiotensin system (RAS) was activated in 5/6 nephrectomized rats and partly deactivated by injection of adenoviruses encoding short hairpin RNA against periostin (sh-periostin). Renal fibrosis in nephrectomized rats and profibrotic transforming growth factor-β-induced epithelial-mesenchymal transition (EMT) and ERK1/2 activation in NRK-52E cells were suppressed by sh-periostin. Moreover, knockdown of periostin decreased the generation of Interleukin 6 (IL6) and tumor necrosis factor-α (TNF-α) and accelerated p62 degradation in the remnant kidneys. Both HK-2 cells treated with recombinant periostin and NRK-52E cells infected with adenoviruses expressing periostin produced more IL6 and TNF-α than control cells and displayed impaired autophagy as evidenced by inhibition of LC3II to LC3I conversion, Beclin 1 expression, and p62 degradation. By treating cells with rapamycin, an inhibitor of mamalian target of rapamycin known to activate autophagy, we noted that periostin-induced inflammation was inhibited. Additionally, HK-2 cells transfected with periostin overexpression plasmid generated more CCL2 and CXCL10, two important chemotactic factors, than untransfected cells. Conditioned medium from HK-2 cells overexpressing periostin augmented chemotaxis of THP-1 macrophages. Collectively, our work demonstrates that knockdown of periostin attenuates 5/6 nephrectomy-induced intrarenal RAS activation, fibrosis, and inflammation in rats. These findings advance our understanding of periostin's role in CKD induced by nephron loss., (© 2019 Wiley Periodicals, Inc.)

Silymarin, an extract from Silybum marianum (milk thistle) containing a standardized mixture of flavonolignans that ameliorates some types of liver disease and, more recently, kidney damage, could be used for the ROS-scavenging effect of these antioxidants. Furthermore, contrast-induced nephropathy (CIN) is an iatrogenic impairment of renal function in patients subjected to angiographic procedures for which there is not yet a successful preventative treatment. Recent evidence has shown that this event is related to tubular/vascular injury activated mainly by oxidative stress. However, whether this bioavailable and pharmacologically safe extract protects against CIN is not clear. We proposed to evaluate the possible protective role of the antioxidant silymarin in an experimental model of CIN. Adult male Swiss mice were separated into 6 groups and pretreated orally with silymarin (50, 200 and 300 mg/kg), N-acetylcysteine (200 mg/kg) or vehicle for 5 days before the CIN and control groups. Renal function was analyzed by plasma creatinine, urea and cystatin C levels. Additionally, blood reactive oxygen species (ROS) were evaluated using ROS bioavailability, protein oxidation and DNA damage. Renal oxidative damage was evaluated using apoptosis/cell viability assays and histological analysis. We showed that silymarin preserved renal function and decreased systemic and renal oxidative damage (antigenotoxic and antiapoptotic properties, respectively) in a dose-dependent manner and was superior to conventional treatment with N-acetylcysteine. Histologically, silymarin treatment also had beneficial effects on renal glomerular and tubular injuries. Therefore, silymarin prophylaxis may be an interesting strategy for the prevention of CIN., (Copyright © 2019. Published by Elsevier Inc.)

Sepsis-associated acute kidney injury (AKI) is a significant problem in critically ill children and adults resulting in increased morbidity and mortality. Fundamental mechanisms contributing to sepsis-associated AKI are poorly understood. Previous research has demonstrated that peroxisome proliferator-activated receptor α (PPARα) expression is associated with reduced organ system failure in sepsis. Using an experimental model of polymicrobial sepsis, we demonstrate that mice deficient in PPARα have worse kidney function, which is likely related to reduced fatty acid oxidation and increased inflammation. Ultrastructural evaluation with electron microscopy reveals that the proximal convoluted tubule is specifically injured in septic PPARα deficient mice. In this experimental group, serum metabolomic analysis reveals unanticipated metabolic derangements in tryptophan-kynurenine-NAD + and pantothenate pathways. We also show that a subgroup of children with sepsis whose genome-wide expression profiles are characterized by repression of the PPARα signaling pathway has increased incidence of severe AKI. These findings point toward interesting associations between sepsis-associated AKI and PPARα-driven fatty acid metabolism that merit further investigation., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Acute kidney injury (AKI) is a serious condition without efficient therapeutic options. Recent studies have indicated that recombinant human a disintegrin and metalloprotease with thrombospondin motifs 13 (rhADAMTS13) provides protection against inflammation. Therefore, we hypothesized that ADAMTS13 might protect against AKI by reducing inflammation. Bilateral renal ischemia-reperfusion injury (I/R) was used as AKI models in this study. Prophylactic infusion of rhADAMTS13 was employed to investigate potential mechanisms of renal protection. Renal function, inflammation, and microvascular endothelial function were assessed after 24 h of reperfusion. Our results showed that I/R mice increased plasma von Willebrand factor levels but decreased ADAMTS13 expression. Administration of rhADAMTS13 to I/R mice recovered renal function, histological injury, and apoptosis. Renal inflammation was reduced by rhADAMTS13, accompanied with the downregulation of p38/extracellular signal-regulated protein kinase phosphorylation and cyclooxygenase-2 expression. rhADAMTS13 restored vasodilation in afferent arterioles in I/R mice. Furthermore, rhADAMTS13 treatment enhanced phosphorylation of Akt at Ser 473 and eNOS at Ser 1177 . Administration of the Akt pathway inhibitor wortmannin reduced the protective effect of rhADAMTS13. Our conclusions are that treatment with rhADAMTS13 ameliorates renal I/R injury by reducing inflammation, tubular cell apoptosis, and improving microvascular endothelial dysfunction. rhADAMTS13 could be a promising strategy to treat AKI in clinical settings.

New Findings: What is the central question of this study? The aim was to determine the renoprotective effects of serelaxin in the setting of chronic heart failure. What are the main findings and its importance? Our data indicate that serelaxin can reduce renal fibrosis and inflammation in experimental heart failure. Currently, there are no effective treatments to rescue renal function in heart failure patients, and our data suggest that serelaxin might have the potential to reduce renal fibrosis and inflammation in heart failure., Abstract: Serelaxin has been demonstrated to attenuate renal fibrosis and inflammation in cardiorenal disease. In the present study, we tested the hypothesis that serelaxin can prevent the decline in renal function in dilated cardiomyopathy (DCM) by targeting renal fibrosis and inflammation. Male transgenic mice with DCM (n = 16) and their wild-type littermates (WT; n = 20) were administered either vehicle or serelaxin (500 μg kg -1  day -1 ; subcutaneous minipumps; 8 weeks). Cardiac function was assessed via echocardiography before and during the eighth week of serelaxin treatment. Renal function and inflammation as well as cardiac and renal fibrosis were assessed at the end of the study. Serelaxin had minimal effect on cardiac function (P ≥ 0.99). Tubulointerstitial and glomerular fibrosis were ∼3-fold greater in vehicle-treated DCM mice compared with vehicle-treated WT mice (P ≤ 0.001). Renal mRNA expression of Tnfα and Il1α were ∼4- and ∼3-fold greater, respectively, in vehicle-treated DCM mice compared with vehicle-treated WT mice (P ≤ 0.05). Tubulointerstitial and glomerular fibrosis were 46 and 45% less, respectively, in serelaxin-treated DCM mice than in vehicle-treated DCM mice (P ≤ 0.01). Renal cortical mRNA expression of Tnfα and Il1α were 56 and 58% less, respectively, in the former group compared with the latter (P ≤ 0.05). The urinary albumin:creatinine ratio was ∼3-fold greater in vehicle-treated DCM mice compared with vehicle-treated WT mice (P = 0.02). The urinary albumin:creatinine ratio was not significantly different between vehicle-treated DCM mice and serelaxin-treated DCM mice (P = 0.38). These data suggest that serelaxin can attenuate renal fibrosis and inflammation and has the potential to exert renoprotective effects in DCM., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)

High levels of serum free fatty acids (FFAs) and proteinuria have been implicated in the pathogenesis of obesity-related nephropathy. CD36, a class B scavenger receptor, is highly expressed in the renal proximal tubules and mediates FFA uptake. It is not clear whether FFA- and proteinuria-mediated CD36 activation coordinates NLRP3 inflammasomes to induce renal tubular injury and inflammation. In this study, we investigated the roles of CD36 and NLRP3 inflammasomes in FFA-induced renal injury in high-fat diet (HFD)-induced obesity. HFD-fed C57BL/6 mice and palmitate-treated HK2 renal tubular cells were used as in vivo and in vitro models. Immunohistochemical staining showed that CD36, IL-1β, and IL-18 levels increased progressively in the kidneys of HFD-fed mice. Sulfo- N-succinimidyl oleate (SSO), a CD36 inhibitor, attenuated the HFD-induced upregulation of NLRP3, IL-1β, and IL-18 and suppressed the colocalization of NLRP3 and ASC in renal tubular cells. In vitro, SSO abolished the palmitate-induced activation of IL-1β, IL-18, and caspase-1 in HK2 proximal tubular cells. Furthermore, treatment with SSO and the knockdown of caspase-1 expression by siRNA both inhibited palmitate-induced cell death and apoptosis in HK2 cells. Collectively, palmitate causes renal tubular inflammation, cell death, and apoptosis via the CD36/NLRP3/caspase-1 axis, which may explain, at least in part, the mechanism underlying FFA-related renal tubular injury. The blockade of CD36-induced cellular processes is therefore a promising strategy for treating obesity-related nephropathy.

The prevalence of gout is relatively high worldwide, and many gout patients suffer from uric acid nephropathy (UAN) concomitantly. ELR-CXC chemokines such as CXCL8 and CXCL1 have a elevated expression in UAN. In this research, a mouse UAN model was established for a 12 week duration, and uric acid-related crystals were observed. CXCL8(3-72)K11R/G31P (G31P) is a mutant protein of CXCL8/interleukin 8 (IL-8), which has been reported to have therapeutic efficacy in both inflammatory diseases and malignancies for it acts as a selective antagonist towards CXCR1/CXCR2. In this study, G31P-treated mice showed declined production of the blood urea nitrogen (BUN) level and urine volume in UAN mice compared with G31P-untreated UAN counterparts. In addition, G31P effectively improved renal fibrosis, and reduced uric acid accumulation and leukocyte infiltration in UAN kidneys. Furthermore, the expressions of CXCL1 and CXCL2 were reduced and the activation of NOD-like receptors protein 3 (NLRP3) was inhibited by G31P treatment. This study has demonstrated that G31P attenuates inflammatory progression in chronic UAN, and plays a renoprotective function., (Copyright © 2018. Published by Elsevier Masson SAS.)

Introduction: Ischemia and reperfusion (IR) is a process inherent to the procedures involved in the transplantation of organs that causes inflammation, cell death and cell injury, and may lead to rejection of the graft. It is possible that the anti-inflammatory properties of the Brazil nuts (BN) can mitigate the renal injury caused by IR., Objective: To investigate whether the previous intake of BN reduces the expression of markers of inflammation, injury, and cell death after renal IR., Methods: Male Wistar rats were distributed into six groups (N = 6/group): SHAM (control), SHAM treated with 75 or 150 mg of BN, IR, and IR treated with 75 or 150 mg of BN. The IR procedure consisted of right nephrectomy and occlusion of the left renal artery with a non-traumatic vascular clamp for 30 min. BN was given daily from day 1 to 7 before surgery (SHAM or IR), and maintained until sacrifice (48 h after surgery). Inflammation was evaluated by renal expression of COX-2 and TGF-β, injury by the expression of vimentin, and cell death by apoptosis through caspase-3 expression (immunohistochemistry)., Results: Pretreatment with 75 mg of BN reduced renal expression of the COX-2, TGF-β, vimentin, and caspase-3. The dose of 150 mg caused increased expression of COX-2., Conclusion: In experimental IR, the damage can be minimized with a prior low-dose intake of BN, improving inflammation, injury, and cell death.

Hypertensive renal damage generally occurs during the middle and late stages of hypertension, which is typically characterized by proteinuria and renal inflammation. Captopril, an angiotensin-converting enzyme (ACE) inhibitor, has been widely used for therapy of arterial hypertension and cardiovascular diseases. However, the protective effects of captopril on hypertension-induced organ damage remain elusive. The present study was designed to explore the renoprotective action of captopril in spontaneously hypertensive rats (SHR). The 6-week-old male SHR and age-matched Wistar-Kyoto rats were randomized into long-term captopril-treated (34 mg/kg) and vehicle-treated groups. The results showed that in SHR there was obvious renal injury characterized by the increased levels of urine albumin, total protein, serum creatinine, blood urea nitrogen, renal inflammation manifested by the increased mRNA and protein expression of inflammatory factors including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and inducible nitric oxide synthase, and enhanced nuclear factor-κB (NF-κB) activation. Captopril treatment could lower blood pressure, improve renal injury, and suppress renal inflammation and NF-κB activation in SHR rats. In conclusion, captopril ameliorates renal injury and inflammation in SHR possibly via inactivation of NF-κB signaling.

Aim: We explored whether Fluorofenidone reduced interleukin-1β (IL-1β) production by interacting with NLRP3 inflammasome in unilateral ureteral obstruction (UUO)., Methods: Ureteral obstruction rats were treated with Fluorofenidone (500 mg/kg per day) for 3, 7 days. Morphologic analysis and leukocytes infiltration were assessed in ligated kidneys. Furthermore, plasmids of NLRP3, ASC, pro-Caspase-1, pro-IL-1β were co-transfected into 293 T cells, and then treated with Fluorofenidone (2 mM). The expression of NLRP3, ASC, pro-caspase-1, cleavage caspase-1, pro-IL-1β and cleavage IL-1β were measured by Western blot or real-time PCR in vivo and in vitro. Moreover the interaction of NLRP3 inflammasome-assembly was detected by co-immunoprecipitation and confocal immunofluorescence., Results: Fluorofenidone treatment significantly attenuated renal fibrosis and leukocytes infiltration in UUO model. Fluorofenidone had no effect on the expression of pro-IL-1β. Interestingly, Fluorofenidone inhibited the activation of NLRP3 inflammasome, downregulated Caspase-1 levels and thereby decreased the cleavage of pro-IL-1β into IL-1β in vivo and in vitro. Fluorofenidone treatment distinctively weakened the interaction between NLRP3 and ASC, as well as ASC and pro-Caspase-1 in vivo. However, Fluorofenidone treatment only significantly weakened the interaction between ASC and pro-Caspase-1 in co-transfected 293 T cells., Conclusion: Fluorofenidone serves as a novel anti-inflammatory agent that attenuates IL-1β production in UUO model by interacting with NLRP3 inflammasome., (© 2017 Asian Pacific Society of Nephrology.)

The aim of this study was to explore the potential effects of quercetin (QUR) on doxorubicin (DOX)-induced nephrotoxicity. Fifty male rats were assigned to five groups (10 rats each): a control group, a DOX-treated group (total dose, 15 mg/kg bw, intraperitoneally), a QUR-treated group (50 mg/kg bw/day, orally), a prophylaxis co-treated group, and a therapeutic co-treated group. Biochemical parameters and renal function were measured. Moreover, kidney tissues were homogenized for inflammatory marker evaluation and real-time qPCR analysis to determine the changes in intermediate filament protein mRNA levels (desmin, vimentin, connexin 43 and nestin). QUR exhibited a significant nephroprotective effect, particularly when it was administered prior to and simultaneously with DOX treatment (prophylaxis co-treated group). This role was biochemically demonstrated by the significant modulation of DOX-induced body weight loss, hypoproteinemia, and elevated serum creatinine and urea. Moreover, QUR attenuated the inflammatory response as shown by decreased renal nitric oxide, tumor necrosis factor-α production and myeloperoxidase activity elicited by DOX injection. These biochemical improvements were accompanied by a significant histopathological restoration of rat kidney tissue and successful down-regulation of the intermediate filament protein mRNA levels, indicating amelioration of DOX-induced podocyte injury. Taken together, these results conclusively demonstrated that QUR administration has a prophylactic effect on DOX-induced injury in the rat kidney., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Renal hypoxia occurs in acute kidney injury (AKI) of various etiologies. Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Preconditional HIF activation protects against AKI, suggesting a new approach in AKI treatment. HIF is degraded under normoxic conditions mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative α-subunits by HIF prolyl hydroxylases (PHD). FG-4592 is a novel, orally active, small-molecule HIF PHD inhibitor for the treatment of anemia in patients with chronic kidney disease (CKD). The current study aimed to evaluate the effect of FG-4592 (Roxadustat) on cis -diamminedichloroplatinum (cisplatin)-induced kidney injury. In mice, pretreatment with FG-4592 markedly ameliorated cisplatin-induced kidney injury as shown by the improved renal function (blood urea nitrogen (BUN), serum creatinine (Scr), and cystatin C) and kidney morphology (periodic acid-Schiff (PAS) staining) in line with a robust blockade of renal tubular injury markers of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Meanwhile, the renal apoptosis and inflammation induced by cisplatin were also strikingly attenuated in FG-4592-treated mice. Along with the protective effects shown above, FG-4592 pretreatment strongly enhanced HIF-1α in tubular cells, as well as the expressions of HIF target genes. FG-4592 alone did not affect the renal function and morphology in mice. In vitro , FG-4592 treatment significantly up-regulated HIF-1α and protected the tubular cells against cisplatin-induced apoptosis. In summary, FG-4592 treatment remarkably ameliorated the cisplatin-induced kidney injury possibly through the stabilization of HIF. Thus, besides the role in treating CKD anemia, the clinical use of FG-4592 also could be extended to AKI., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Necrotizing glomerular lesions are a feature of severe glomerulonephritis. Unlike apoptosis, cellular necrosis has the potential to release damage-associated proteins into the microenvironment, thereby potentiating inflammation. Until recently necrosis was thought to be an unregulated cellular response to injury. However, recent evidence suggests that under certain circumstances receptor mediated necrosis occurs in response to death ligand signalling, one form of which is termed necroptosis. RIPK3, a receptor interacting protein, is a limiting step in the intracellular signalling pathway of necroptosis. A non-redundant role for RIPK3 has been implicated in mouse models of renal ischaemia reperfusion injury and toxic renal injury. The aim of this study was to investigate the role of RIPK3 in nephrotoxic nephritis (NTN), a model of immune complex glomerulonephritis in mice., Methods: We induced NTN in RIPK3-/- and WT mice, comparing histology and renal function in both groups., Results: There was no improvement in urinary albumin creatinine ratio, serum urea, glomerular thrombosis or glomerular macrophage infiltration in the RIPK3-/- mice compared to WT. There was also no difference in number of apoptotic cells in glomeruli as measured by TUNEL staining between the RIPK3-/- and WT mice., Conclusion: The data suggests that RIPK3 is not on a critical pathway in the pathogenesis of nephrotoxic nephritis.

Background: Diabetic nephropathy (DN) is a major microvascular complication in diabetes. An increasing body of evidence has shown that DN is related to chronic inflammation, kidney hypertrophy, and fibrosis. While thalidomide has been shown to have anti-inflammatory and antifibrotic effects, the effects of thalidomide on the pathogenesis of DN are unclear. This study was undertaken to explore whether thalidomide has renal-protective effects in diabetic rats., Methods: Male Sprague Dawley rats were injected intraperitoneally with 50 mg/kg streptozotocin to induce diabetes. Diabetic rats were treated with thalidomide (200 mg/kg/d) for 8 weeks, and then blood and urine were collected for measurement of renal function-related parameters. Histopathology, immunohistochemistry, enzyme-linked immunosorbent assay, and Western blot analyses were performed to assess renal proinflammatory cytokines, fibrotic protein, and related signaling pathways., Results: Diabetic rats exhibited obvious renal structural and functional abnormalities, as well as renal inflammation and fibrosis. Compared with diabetic control rats, those treated with thalidomide showed significantly improved histological alterations and biomarkers of renal function, as well as reduced expression of renal inflammatory cytokines, including NF-κB and MCP-1. Furthermore, renal fibrotic proteins, such as TGF-β1, TβRII, TβRI, smad3, collagen IV, and fibronectin were also remarkably suppressed. Treatment with thalidomide markedly stimulated the phosphorylation of AMPKα., Conclusion: In this study, thalidomide suppressed the inflammatory and fibrotic processes in DN. These effects were partly mediated by the activation of AMPKα, and inhibition of the NF-κB/MCP-1 and TGF-β1/Smad signaling pathways. These results suggest that thalidomide may have therapeutic potential in diabetic renal injury through the anti-inflammatory pathway., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Several studies have shown that cadmium (Cd) induces nephrotoxicity and many plant foods phytochemicals have been found useful but their possible mechanism of action still remains unexplored. Hence, this study aimed to investigate the nephroprotective effect of essential oils from Nigeria ginger and turmeric rhizomes in cadmium-treated rats by examining their effect on renal function biomarkers (creatinine, urea and BUN), inflammatory cytokines (IL-6, IL-10 and TNF-Alpha) and renal adenosine deaminase (ADA) activity. The result revealed that essential oils from ginger and turmeric rhizomes exert anti-inflammatory effect by preventing alterations of renal function markers and cytokines (IL-6, IL-10 and TNF-Alpha) levels in Cd-treated rats. In addition, the essential oils inhibited renal ADA activity in Cdtreated rats. In conclusion, inhibition of ADA activity and modulation of inflammatory cytokines could be suggested as the possible mechanism of action by which essential oils from ginger and turmeric rhizomes exert their nephroprotective activities.

Ginsenoside Rg1, one of the most notable active components of Panax ginseng, has been widely reported to exert anti-inflammatory actions. This study aimed to reveal whether ginsenoside Rg1 also exhibits beneficial roles against lipopolysaccharide (LPS)-induced apoptosis and inflammation in human renal tubular epithelial cells, and to evaluate the potential role of the component on tubulointerstitial nephritis treatment. HK-2 cells were treated with various doses of ginsenoside Rg1 (0, 50, 100, 150, and 200 μM) in the absence or presence of 5 μg/mL LPS. Thereafter, CCK-8 assay, flow cytometry, western blot, migration assay, reactive oxygen species (ROS) assay, and ELISA were carried out to respectively assess cell viability, apoptosis, migration, ROS activity, and the release of inflammatory cytokines. As a result, ginsenoside Rg1 protected HK-2 cells from LPS-induced injury, as cell viability was increased, cell apoptosis was decreased, and the release of MCP-1, IL-1β, IL-6, and TNF-α was reduced. Ginsenoside Rg1 functioned to HK-2 cells in a dose-dependent manner, and the 150 μM dose exhibited the most protective functions. Ginsenoside Rg1 had no significant impact on cell migration and ROS activity, while it alleviated LPS-induced ROS release and migration impairment. Furthermore, the down-regulations of p-PI3K, p-AKT, and up-regulations of PTEN, p-IκBα, p-p65, Bcl-3 induced by LPS were recovered to some extent after ginsenoside Rg1 treatment. In conclusion, ginsenoside Rg1 protects HK-2 cells against LPS-induced inflammation and apoptosis via activation of the PI3K/AKT pathway and suppression of NF-κB pathway.

Obesity is a major and independent risk factor of kidney diseases. The pathogenic mechanisms of obesity-associated renal injury are recognized to at least involve a lipid-rich and pro-inflammatory state of the renal tissues, but specific mechanisms establishing causal relation remain unknown. Saturated fatty acids are elevated in obesity, and known to induce chronic inflammation in kidneys. Myeloid differentiation protein 2 (MD2) is an important protein in lipopolysaccharide-induced innate immunity response and inflammation. We suggested that obesity-associated renal injury is regulated by MD2 thereby driving an inflammatory renal injury. The used three mouse models for in vivo study: MD2 knockout mice (KO) maintained on high fat diet (HFD), wild-type mice on HFD plus L6H21, a specific MD2 inhibitor and KO mice given palmitic acid (PA) by IV injection. The in vitro studies were carried out in cultured renal tubular epithelial cells, mouse mesangial cells and primary macrophages, respectively. The HFD mice presented with increased hyperlipidemia, serum creatinine and proteinuria. Renal tissue from HFD mice had increased fibrosis, inflammatory cytokines, macrophage infiltration, and activation of NF-κB and MAPKs. This HFD-induced renal injury profile was not observed in KO mice or L6H21-treated mice. Mice given PA mimmicked the HFD-induced renal injury profiles, which were prevented by MD2 knockout. The in vitro data further confirmed MD2 mediates PA-induced inflammation. MD2 is causally related with obesity-associated renal inflammatory injury. We believe that MD2 is an attractive target for future therapeutic strategies in obesity-associated kidney diseases., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: Cisplatin is a potent chemotherapeutic drug whose nephrotoxic effect is a major complication and a dose-limiting factor for antitumoral therapy. There is much evidence that inflammation contributes to the pathogenesis of cisplatin-induced nephrotoxicity. We found that cilastatin, a renal dehydropeptidase-I inhibitor, has protective effects in vitro and in vivo against cisplatin-induced renal damage by inhibiting apoptosis and oxidation. Here, we investigated the potential use of cilastatin to protect against cisplatin-induced kidney injury and inflammation in rats., Methods: Male Wistar rats were divided into four groups: control, cilastatin-control, cisplatin and cilastatin-cisplatin. Nephrotoxicity was assessed 5 days after administration of cisplatin based on blood urea nitrogen, creatinine, glomerular filtration rate (GFR), kidney injury molecule (KIM)-1 and renal morphology. Inflammation was measured using the electrophoretic mobility shift assay, immunohistochemical studies and evaluation of inflammatory mediators., Results: Compared with the control rats, cisplatin-administered rats were affected by significant proximal tubule damage, decreased GFR, increased production of inflammatory mediators and elevations in urea, creatinine and tissue KIM-1 levels. Cilastatin prevented these changes in renal function and ameliorated histological damage in cisplatin-administered animals. Cilastatin also reduced pro-inflammatory cytokine levels, activation of nuclear factor-κB and CD68-positive cell concentrations., Conclusions: Cilastatin reduces cisplatin-induced nephrotoxicity, which is associated with decreased inflammation in vivo. Although the exact role of decreased inflammation in nephroprotection has not been fully elucidated, treatment with cilastatin could be a novel strategy for the prevention of cisplatin-induced acute kidney injury., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) plays a critical role in the regulation of blood pressure and fluid volume homeostasis. Mice lacking functional Npr1 (coding for GC-A/NPRA) exhibit hypertension and congestive heart failure. However, the underlying mechanisms remain largely less clear. The objective of the present study was to determine the physiological efficacy and impact of all- trans -retinoic acid (ATRA) and sodium butyrate (NaBu) in ameliorating the renal fibrosis, inflammation, and hypertension in Npr1 gene-disrupted haplotype (1-copy; +/-) mice (50% expression levels of NPRA). Both ATRA and NaBu, either alone or in combination, decreased the elevated levels of renal proinflammatory and profibrotic cytokines and lowered blood pressure in Npr1 +/- mice compared with untreated controls. The treatment with ATRA-NaBu facilitated the dissociation of histone deacetylase (HDAC) 1 and 2 from signal transducer and activator of transcription 1 (STAT1) and enhanced its acetylation in the kidneys of Npr1 +/- mice. The acetylated STAT1 formed a complex with nuclear factor-κB (NF-κB) p65, thereby inhibiting its DNA-binding activity and downstream proinflammatory and profibrotic signaling cascades. The present results demonstrate that the treatment of the haplotype Npr1 +/- mice with ATRA-NaBu significantly lowered blood pressure and reduced the renal inflammation and fibrosis involving the interactive roles of HDAC, NF-κB (p65), and STAT1. The current findings will help in developing the molecular therapeutic targets and new treatment strategies for hypertension and renal dysfunction in humans., (Copyright © 2017 the American Physiological Society.)

Mesenchymal stem/stromal cells (MSCs) have distinct capability for renal repair, but may have safety concerns. MSC-derived extracellular vesicles emerged as a novel noncellular alternative. Using a porcine model of metabolic syndrome and renal artery stenosis we tested whether extracellular vesicles attenuate renal inflammation, and if this capacity is mediated by their cargo of the anti-inflammatory cytokine interleukin (IL) 10. Pigs with metabolic syndrome were studied after 16 weeks of renal artery stenosis untreated or treated four weeks earlier with a single intrarenal delivery of extracellular vesicles harvested from adipose tissue-derived autologous MSCs. Lean and sham metabolic syndrome animals served as controls (seven each). Five additional pigs with metabolic syndrome and renal artery stenosis received extracellular vesicles with pre-silenced IL10 (IL10 knock-down). Single-kidney renal blood flow, glomerular filtration rate, and oxygenation were studied in vivo and renal injury pathways ex vivo. Retention of extracellular vesicles in the stenotic kidney peaked two days after delivery and decreased thereafter. Four weeks after injection, extracellular vesicle fragments colocalized with stenotic-kidney tubular cells and macrophages, indicating internalization or fusion. Extracellular vesicle delivery attenuated renal inflammation, and improved medullary oxygenation and fibrosis. Renal blood flow and glomerular filtration rate fell in metabolic syndrome and renal artery stenosis compared to metabolic syndrome, but was restored in pigs treated with extracellular vesicles. These renoprotective effects were blunted in pigs treated with IL10-depleted extracellular vesicles. Thus, extracellular vesicle-based regenerative strategies might be useful for patients with metabolic syndrome and renal artery stenosis., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

It has been reported that changes in cytokine levels affect mitochondrial functions, levels of hypoxia-inducible factor α (HIF-1α), and tissue damage during sepsis. We aimed to investigate the effects of simvastatin pretreatment on mitochondrial enzyme activities, and on levels of ghrelin, HIF-1α, and thiobarbituric acid reactive substances (TBARS) in kidney tissue during sepsis. Rats were separated into four groups, namely, control, lipopolysaccharides (LPS) (20 mg/kg), simvastatin (20 mg/kg), and simvastatin + LPS. We measured the levels of mitochondrial enzyme activities and TBARS in the kidney using spectrophotometry. The histological structure of the kidney sections was examined after staining with hematoxylin and eosin. Tumor necrosis factor α (TNF-α), IL-10, HIF-1α, and ghrelin immunoreactivity were examined using proper antibodies. In tissue, TNF-α (p < 0.01) and HIF-1α (p < 0.05) levels were increased in the simvastatin + LPS and LPS groups. TBARS levels were higher in the LPS group than in the other groups (p < 0.01), but they were similar in the simvastatin + LPS and control groups (p > 0.05). Ghrelin immunoreactivity was lower in the LPS group (p < 0.05) and higher in the simvastatin + LPS group than in the LPS group (p < 0.01). We observed tubular damage in the sections of the LPS group. There were no differences in mitochondrial enzyme activities between the groups (p > 0.05). We observed that pretreatment of simvastatin caused favorable changes on ghrelin and TBARS levels in rats with sepsis.

This work investigated the capacity of (-)-epicatechin to prevent the renal damage induced by LPS administration in rats. Male Sprague Dawley rats were fed for 4 days a diet without or with supplementation with (-)-epicatechin (80mg/kg BW/d), and subsequently i.p. injected with lipopolysaccharide (LPS). Six hours after injection, LPS-treated rats exhibited increased plasma creatinine and urea levels as indicators of impaired renal function. The renal cortex of the LPS-treated rats showed: i) increased expression of inflammatory molecules (TNF-α, iNOS and IL-6); ii) activation of several steps of NF-κB pathway; iii) overexpression of TLR4, and iv) higher superoxide anion production and lipid peroxidation index in association with increased levels of gp91 phox and p47 phox (NOX2) and NOX4. Pretreatment with dietary (-)-epicatechin prevented the adverse effects of LPS challenge essentially by inhibiting TLR4 upregulation and NOX activation and the consequent downstream events, e.g. NF-kB activation., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

This study investigated the pretreatment and post-treatment effects of dipyridamole (20 mg/kg/day, p.o.) in gentamicin-induced acute nephrotoxicity in rats. Rats were administered gentamicin (100 mg/kg/day, i.p.) for 8 days. Gentamicin-administered rats exhibited renal structural and functional changes as assessed in terms of a significant increase in serum creatinine and urea and kidney weight to body weight ratio as compared to normal rats. Renal histopathological studies revealed a marked incidence of acute tubular necrosis in gentamicin-administered rats. These renal structural and functional abnormalities in gentamicin-administered rats were accompanied with elevated serum uric acid level, and renal inflammation as assessed in terms of decrease in interleukin-10 levels. Dipyridamole pretreatment in gentamicin-administered rats afforded a noticeable renoprotection by markedly preventing renal structural and functional abnormalities, renal inflammation and serum uric acid elevation. On the other hand, dipyridamole post-treatment did not significantly prevent uric acid elevation and renal inflammation, and resulted in comparatively less protection on renal function although it markedly reduced the incidence of tubular necrosis. In conclusion, uric acid elevation and renal inflammation could play key roles in gentamicin-nephrotoxicity. Dipyridamole pretreatment markedly prevented gentamicin-induced acute nephrotoxicity, while its post-treatment resulted in comparatively less renal functional protection., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Aminophylline increases the intracellular concentration of cAMP and exerts an anti-inflammatory effect. The aim of this study was to investigate the effect of aminophylline on renal ischemia-reperfusion (I/R) injury in mice., Methods: Thirty C57BL/6 mice were divided into 3 groups. In the sham group (group S, n = 10), only right nephrectomy was performed. In the control group (group C, n = 10), after right nephrectomy, the mice were subjected to 30 minutes of left renal ischemia. In the aminophylline group (group A, n = 10), an intraperitoneal injection of aminophylline (5 mg/kg) was performed before renal ischemia. Twenty-four hours after reperfusion, the mice were euthanized, and plasma and kidney samples were obtained to analyze the serum creatinine, renal histology, and expression levels of nuclear factor-kappa B (NF-kB) and pro-inflammatory cytokines., Results: The serum creatinine concentration in group C was markedly elevated at 24 hours after reperfusion. Aminophylline treatment significantly reduced serum creatinine, compared with group C. Aminophylline also reduced the histological evidence of renal damage. The expression levels of NF-kB, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), and intercellular adhesion molecule-1 (ICAM-1) mRNA were significantly increased in group C (P < .001). Group A showed lower expression of NF-kB, TNF-α, MCP-1, MIP-2, and ICAM-1 mRNA than group C (P < .01)., Conclusions: Aminophylline treatment improved the renal function and indexes of renal inflammation, which suggests that it provided reno-protection against renal I/R injury., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background/aims: Obese patients and experimental animals exhibit high levels of inflammatory cytokines, such as tumor necrosis factor (TNF)-α. However, the role of TNF-α in the pathophysiologic process in obesity induced kidney damage is still unknown., Methods: We used TNF-α deficient mice and wild-type (WT) C57/BJ6 mice controls to study the effect of TNF-α on inflammation and oxidative stress in kidney by the model of high-fat diet (HFD) and primary isolated mouse renal proximal tubule cells treated with a mixture of free fatty acids (FFA)., Results: Compared with the chow diet group, HFD-fed WT mice had higher urinary albumin and increased levels of renal fibrosis, glomerulosclerosis, inflammation, oxidative stress and apoptosis in the kidney. These changes were co-related with increased expression of TNF-α in the kidney and were attenuated by TNF-α deficiency. In vitro, accumulation of intracellular lipids induced TNF-α expression and oxidative stress in FFA treated primary proximal tubule cells. However, TNF-α inhibition with siRNA or TNF-α deficiency decreased the lipid induced oxidative stress in these cells., Conclusion: These findings suggest that TNF-α plays an important role in the HFD induced kidney damage, and targeting TNF-α and/or its receptors could be a promising therapeutic regimen for progressive nephropathy., (© 2017 The Author(s). Published by S. Karger AG, Basel.)

Aims: The study aimed to investigate the renoprotective effect of glucagon-like peptide-1 (GLP-1) against renal tubular injury in C57BL/6 mice induced by a high-fat diet (HFD)., Methods: Twenty C57BL/6 mice were fed HFD for 12 weeks. Ten of these mice were treated with GLP-1 at 200 µg/kg subcutaneously twice daily for 4 weeks (HFDG group), and the other ten mice received vehicle only (HFD group). Ten mice fed standard rodent chow served as controls (Con group). Body weight, kidney weight, food intake, and systolic blood pressure were measured. The expression of endoplasmic reticulum stress (ERS) markers (BIP, p-eIF2α, ATF4, and CHOP) and apoptosis in the kidney were examined utilizing western blotting, immunohistochemistry and TUNEL, respectively. Angiotensin II and angiotensin II type 1 receptor (AT1R) were examined by ELISA. Human proximal tubule epithelial cells (HK2) were treated with GLP-1(150 nM) followed by treatment with palmitic acid (500 nM [PA]) for 24 h. HK2 cells treated with BSA were used as controls. The protein levels of ERS markers, apoptosis-associated protein, and AT1R were measured by western blotting., Results: Increase of body weight, food intake, and systolic blood pressure was less pronounced in GLP-1 treated HFDG mice compared to HFD mice. The levels of ERS markers (BIP, p-eIF2α, ATF4, and CHOP) and apoptosis decreased following GLP-1 treatment in vivo and in vitro (p<0.05). Increased AT1R induced by HFD and PA were blocked with GLP-1 treatment. In contrast, the level of angiotensin II after GLP-1 treatment was not significantly different between the HFD and HFDG mice., Conclusion: The study indicated that saturated fatty acids induced ERS and apoptosis in the kidney and increased AT1R expression. GLP-1 treatment exerted renoprotective effects against saturated fatty acid-induced kidney tubular cell ERS and apoptosis together with inhibition of AT1R expression in vivo and in vitro., (© 2017 The Author(s)Published by S. Karger AG, Basel.)

Gentamicin is a commonly used aminoglycoside antibiotic. However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exerts lipid-lowering effects, antioxidant, anti-inflammatory as well as anti-apoptotic effects, this study aimed to investigate the protective effects of atorvastatin against gentamicin-induced nephrotoxicity. Male Sprague Dawley rats were used and nephrotoxicity was induced by intraperitoneal injection of gentamicin, 100 mg/kg/day, for 15 days. Atorvastatin, 10 mg/kg/day, was administered by orally gavage 30 min before gentamicin injection on day 1 to 15 (pretreatment) or on day 10 to15 (delayed treatment). For only atorvastatin treatment group, it was given on day 1 to 15. At the end of the experiment, kidney weight, blood urea nitrogen and serum creatinine as well as renal inflammation (NF-κB, TNFαR1, IL-6 and iNOS), renal fibrosis (TGFβ1), ER stress (calpain, GRP78, CHOP, and caspase 12) and apoptotic markers (cleaved caspase-3, Bax, and Bcl-2) as well as TUNEL assay were determined. Gentamicin-induced nephrotoxicity was confirmed by marked elevations in serum urea and creatinine, kidney hypertrophy, renal inflammation, fibrosis, ER stress and apoptosis and attenuation of creatinine clearance. Atorvastatin pre and delayed treatment significantly improved renal function and decreased renal NF-κB, TNFαR1, IL-6, iNOS and TGFβ1 expressions. They also attenuated calpain, GRP78, CHOP, caspase 12, Bax, and increased Bcl-2 expressions in gentamicin-treated rat. These results indicate that atorvastatin treatment could attenuate gentamicin-induced nephrotoxicity in rats, substantiated by the reduction of inflammation, ER stress and apoptosis. The effect of atorvastatin in protecting from renal damage induced by gentamicin seems to be more effective when it beginning given along with gentamicin or pretreatment., Competing Interests: The authors have declared that no competing interests exist.

Transforming growth factor beta 1 (TGF-β1) is one of the most studied cytokines involved in renal tubulo-interstitial fibrosis, which is characterized by myofibroblast abundance and proliferation, and high buildup of extracellular matrix in the tubular interstitium leading to organ failure. Endoglin (Eng) is a 180-kDa homodimeric transmembrane protein that regulates a great number of TGF-β1 actions in different biological processes, including ECM synthesis. High levels of Eng have been observed in experimental models of renal fibrosis or in biopsies from patients with chronic kidney disease. In humans and mice, two Eng isoforms are generated by alternative splicing, L-Eng and S-Eng that differ in the length and composition of their cytoplasmic domains. We have previously described that L-Eng overexpression promotes renal fibrosis after unilateral ureteral obstruction (UUO). However, the role of S-Eng in renal fibrosis is unknown and its study would let us analyze the possible function of the cytoplasmic domain of Eng in this process. For this purpose, we have generated a mice strain that overexpresses S-Eng (S-ENG(+)) and we have performed an UUO in S-ENG(+) and their wild type (WT) control mice. Our results indicate that obstructed kidney of S-ENG(+) mice shows lower levels of tubulo-interstitial fibrosis, less inflammation and less interstitial cell proliferation than WT littermates. Moreover, S-ENG(+) mice show less activation of Smad1 and Smad2/3 pathways. Thus, S-Eng overexpression reduces UUO-induced renal fibrosis and some associated mechanisms. As L-Eng overexpression provokes renal fibrosis we conclude that Eng-mediated induction of renal fibrosis in this model is dependent on its cytoplasmic domain., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Despite considerable advances in the understanding of systemic lupus erythematosus (SLE), there is still an urgent need for new and more targeted treatment approaches. We previously demonstrated that small-molecule blockade of G protein βγ subunit (Gβγ) signaling inhibits acute inflammation through inhibition of chemokine receptor signal transduction. We undertook this study to determine whether inhibition of Gβγ signaling ameliorates disease in a mouse model of SLE., Methods: Lupus-prone (NZB × NZW)F1 female mice were prophylactically or therapeutically treated with the small-molecule Gβγ inhibitor gallein. Tissue samples were analyzed by flow cytometry and immunohistochemistry. The development and extent of nephritis were assessed by monitoring proteinuria and by immunohistochemical analysis. Serum immunoglobulin levels were measured by enzyme-linked immunosorbent assay, and total IgG and anti-double-stranded DNA (anti-dsDNA) antibody-secreting cells were measured by enzyme-linked immunospot assay., Results: Gallein inhibited accumulation of T cells and germinal center (GC) B cells in the spleen. Both prophylactic and therapeutic treatment reduced GC size, decreased antibody-secreting cell production in the spleen, and markedly decreased accumulation of autoreactive anti-dsDNA antibody-secreting cells in kidneys. Gallein also reduced immune complex deposition in kidneys. Finally, gallein treatment dramatically inhibited kidney inflammation, prevented glomerular damage, and decreased proteinuria. Mechanistically, gallein inhibited immune cell migration and signaling in response to chemokines in vitro, which suggests that its mechanisms of action in vivo are inhibition of migration of immune cells to sites of inflammation and inhibition of immune cell maturation., Conclusion: Overall, these data demonstrate the potential use of gallein or novel inhibitors of Gβγ signaling in SLE treatment., (© 2016, American College of Rheumatology.)

The pathogenesis of cisplatin-induced acute kidney injury (AKI) is characterized by tubular cell apoptosis and inflammation. However, the molecular mechanisms are not fully understood. We found that CXCL16 was induced in renal tubular epithelial cells in response to cisplatin-induced AKI. Therefore, we investigated whether CXCL16 played a role in cisplatin-induced tubular cell apoptosis and inflammation. Wild-type and CXCL16 knockout mice were administrated with vehicle or cisplatin at 20 mg/kg by intraperitoneal injection. CXCL16 knockout mice had lower blood urea nitrogen and less tubular damage following cisplatin-induced AKI as compared with wild-type mice. Genetic disruption of CXCL16 reduced tubular epithelial cell apoptosis and decreased caspase-3 activation. Furthermore, CXCL16 deficiency inhibited infiltration of macrophages and T cells into the kidneys following cisplatin treatment, which was associated with reduced expression of the proinflammatory cytokines in the kidneys. Taken together, our results indicate that CXCL16 plays a crucial role in the pathogenesis of cisplatin-induced AKI through regulation of apoptosis and inflammation and maybe a novel therapeutic target for cisplatin-induced AKI., Competing Interests: None