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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.)

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.

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.)

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.)

Currently, the number of imaging and interventional procedures that use contrast agents (CAs) is gradually increasing. Contrast-induced nephropathy (CIN) is the most important CA-related complication. Oxidative stress plays a significant role in its pathophysiology. Lycopene (LPN) is a natural substance with strong antioxidant capacity. The present study aimed to investigate the potential preventive effects of LPN against CIN. In total, 28 male Wistar albino rats were divided into 4 groups with 7 rats in each group; the groups include normal control group, LPN only group at a dose of 4 mg/kg/day for 10 days, CIN group by administering 10 mg/kg furosemide IM + 10 mg/kg indomethacin IP + 10 ml/kg iomeprol IV following 24-h dehydration, and CIN + LPN group. There were statistically significant increase in urea, creatinine, and malondialdehyde levels (p < 0.001, for all) but a significant decrease in glutathione, superoxide dismutase, catalase, and glutathione peroxidase levels (p < 0.001, for all) in the CIN group compared with the control group. On histological examination, a significant increase of infiltrated inflammatory cells and necrotic degenerative changes were observed in the CIN group and the immunohistochemical examination revealed a significant increase in inflammation (inducible nitric oxide synthase), autophagy (LC3/B), and apoptosis (cleaved caspase 3) in the CIN group compared with the control group (p < 0.05, for all). Significant improvements in these unfavorable parameters were observed with CIN + LPN group compared with the CIN only group. In conclusion, the favorable effects of LPN as an anti-inflammatory, antiautophagic, and antiapoptotic agent in an experimental model of CIN have been demonstrated., (© The Author(s) 2014.)

Background: Nitric oxide (NO) deficiency occurs in humans and animals with hypertension and chronic kidney disease (CKD). An inhibitor of NO synthase, N(G)-nitro-l-arginine methyl ester (L-NAME) exacerbates kidney damage in the adult spontaneously hypertensive rat (SHR). We examined whether L-NAME exacerbated hypertensive nephrosclerosis in young SHRs and whether melatonin protects SHRs against kidney damage by restoration of the asymmetric dimethylarginine (ADMA)-NO pathway., Methods: Rats aged 4 weeks were randomly assigned into three groups (n = 10 for each group): Group 1 (control), SHRs without treatment; Group 2 (L-NAME), SHRs received L-NAME (80 mg/L) in drinking water; and Group 3 (L-NAME + melatonin), SHRs received L-NAME (80 mg/L) and 0.01% melatonin in drinking water. All rats were sacrificed at 10 weeks of age., Results: L-NAME exacerbates the elevation of blood pressure, renal dysfunction, and glomerular sclerosis in young SHRs. L-NAME induced an increase of ADMA and a decrease of arginine-to-ADMA ratio in the SHR kidney. Melatonin therapy prevented L-NAME-exacerbated hypertension and nephrosclerosis in young SHRs. In addition, melatonin restored L-NAME-induced reduction of dimethylarginine dimethylaminohydrolase (DDAH; ADMA-metabolizing enzymes) activity in the SHR kidney. Next, melatonin decreased renal ADMA concentrations, increased renal arginine-to-ADMA ratio, and restored NO production in L-NAME-treated young SHRs. Moreover, melatonin reduced the degree of oxidative damaged DNA product, 8-hydroxydeoxyguanosine immunostaining in L-NAME-treated SHR kidney., Conclusion: Our results indicated that L-NAME/SHR is a useful model for hypertensive nephrosclerosis in young rats. The blood pressure-lowering and renoprotective effects of melatonin is due to increases of DDAH activity, decreases of ADMA, and reduction of oxidative stress in L-NAME-treated SHR kidney. Specific therapy targeting the DDAH-ADMA pathway may be a promising approach to slowing chronic kidney disease progression in children., (Copyright © 2013. Published by Elsevier B.V.)

Background: Currently, the number of imaging and interventional procedures that use contrast agents (CAs) is gradually increasing. Oxidative stress plays a significant role in its pathophysiology. Curcumin (CC) is a natural substance with strong antioxidant efficacy., Materials and Methods: In total, 24 male Wistar-albino rats were divided into four groups with seven rats in each group., Results: Biochemical measurements showed a significant increase (p < 0.001) in urea, creatinine and malondialdehyde (MDA) but a significant decrease (p < 0.001) in glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) levels in the contrast-induced nephropathy (CIN) group compared with the control group. The immunohistochemical examination revealed a significant increase in autophagic and apoptotic cell death ratios and in the inflammatory signal (p < 0.05). Compared with the CIN group, a significant improvement in these unfavorable parameters was observed with CC therapy., Conclusions: The preventive efficacy of CC against an experimental model of CIN has been demonstrated.

Baicalin, a herb-derived flavonoid compound, has beneficial activities, including the modulation of oxidative stress and inflammation. Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated transcription factor that plays an important role in regulating nuclear factor-κB (NF-κB)-induced age-related inflammation. We investigated the anti-inflammatory action of baicalin, which depends on its ability to activate PPARγ, and subsequently to suppress NF-κB. We examined baicalin-treated kidney tissue from 24-month-old Fischer 344 aged rats (10 or 20 mg/kg/day for 10 days) and baicalin-fed mice (10 mg/kg/day for 3 days) for in vivo investigations, and used endothelial YPEN-1 cells for in vitro studies. In the baicalin-fed aged rats, there was a marked enhancement of both nuclear protein levels and DNA binding activity of PPARγ, and a decreased expression of NF-κB target genes (VCAM-1, IL-1β, and IL-6) compared with non-baicalin-fed aged rats. Furthermore, to confirm the anti-inflammatory action of PPARγ activated by baicalin, we used lipopolysaccharide (LPS)-treated cells and mice. The results showed that baicalin induced PPARγ-selective activation in YPEN-1 cells, and that the effects of baicalin were blocked by the PPARγ receptor antagonist, GW9662. In addition, baicalin treatment prevented RS generation, NF-κB activation and the expression of pro-inflammatory genes, whereas it increased PPARγ expression in LPS-treated cells and mouse kidney. Our data suggest that baicalin-induced PPARγ expression reduced age-related inflammation through blocking pro-inflammatory NF-κB activation. These results indicate that baicalin is a novel PPARγ activator and that this agent may have the potential to minimize inflammation.

Alpha-lipoic acid (ALA) is a powerful antioxidant, and its effect in ameliorating complications of diabetes mellitus has been widely documented. The aim of this study was to investigate the role of ALA in the disease progression of remnant kidneys (RK). Systolic blood pressure (SBp), hemoglobin, renal function, kidney malondialdehyde (MDA), glutathione (GSH), vitamin E (Vit E) concentrations, p65 nuclear factor (NF)-κB activity, and macrophage infiltration were analyzed in sham and RK rats supplemented with ALA (100 mg/kg body weight, i.p., every other day) or vehicle for 12 weeks. RK rats exhibited increases in SBp, kidney MDA concentration, p65 NF-κB activity, and macrophage infiltration, which were prominent in weeks 4 and 8 and decreased at week 12. RK rats also showed anemia, microalbuminuria, and decreased renal function and kidney GSH and Vit E concentrations. These changes were all attenuated by 8 weeks of ALA treatment compared to RK vehicle group. But the continued ALA treatment after week 8 reversed the beneficial effect on SBp, kidney MDA concentration, p65 NF-κB activity, macrophage infiltration, anemia, microalbuminuria, and renal function, while the beneficial effect was maintained if the treatment was discontinued after week 8. Furthermore, ALA increased albuminuria and kidney MDA concentration in sham animals. In conclusion, ALA administration attenuates oxidative stress, inflammation, and hypertension and delayed the deterioration of kidney function in RK rats with enhanced oxidative stress, while in healthy animals or RK rats with a well-balanced redox state, ALA may act as a pro-oxidant, contributing to renal dysfunction.

Diabetic nephropathy is a serious complication for diabetic patients, yet the precise mechanism that underlies the development of diabetic complications remains unknown. We hypothesised that dietary antioxidant supplementation with single N-acetylcysteine (NAC) or vitamin C combined with either vitamin E or vitamin E and NAC improves diabetic renal inflammation through the modulation of blood glucose levels, oxidative stress and inflammatory response. Experimental animals were treated with alloxan monohydrate to induce diabetes. Mice were divided into five groups and supplemented with single or a combination of antioxidants. Body weights and blood glucose levels were measured once a week. After 8 weeks of dietary antioxidant supplementation, mice were killed and blood urea N (BUN) and plasma creatinine levels were measured to evaluate renal function. NF-κB protein was indirectly demonstrated by the phosphorylated IκBα (pIκBα) level, and the expressions of oxidative stress- and inflammatory response-related proteins were also determined. We demonstrated that dietary antioxidant supplementation decreased lipid peroxidation levels demonstrated by thiobarbituric acid-reacting substances, BUN and plasma creatinine levels in diabetic kidneys. Moreover, dietary antioxidant cocktail supplementation improved blood glucose levels and selectively regulated the expressions of Cu-Zn superoxide dismutase, haeme oxygenase-1, pIκBα, inducible NO synthase, cyclo-oxygenase-2 and C-reactive protein in diabetic kidneys effectively. These findings demonstrated that diabetic renal failure was associated with inflammatory responses induced by hyperglycaemia. In addition, results in the study suggest that antioxidant cocktail supplementation may have beneficial effects on diabetic nephropathy through selective reduction of blood glucose levels and inflammatory response.

The aim of this work was to study the role of local intrarenal angiotensin II (Ang II) and the oxidative stress in the up-regulation of pro-inflammatory cytokines expression observed in rats submitted to an acute sodium overload. Sprague-Dawley rats were infused for 2 h with isotonic saline solution (Control group) and with hypertonic saline solution alone (Na group), plus the AT1 receptor antagonist losartan (10 mg kg(-1) in bolus) (Na-Los group), or plus the superoxide dismutase mimetic tempol (0.5 mg min(-1) kg(-1)) (Na-Temp group). Mean arterial pressure, glomerular filtration rate, and fractional sodium excretion (FE(Na)) were measured. Ang II, NF-kappaB, hypoxia inducible factor-1 alpha (HIF-1 alpha), transforming growth factor beta1 (TGF-beta1), smooth muscle actin (alpha-SMA), endothelial nitric oxide synthase (eNOS), and RANTES renal expression was evaluated by immunohistochemistry. Ang II, NF-kappaB, and TGF-beta1 and RANTES early inflammatory markers were overexpressed in Na group, accompanied by enhanced HIF-1 alpha immunostaining, lower eNOS expression, and unmodified alpha-SMA. Losartan and tempol increased FE(Na) in sodium overload group. Although losartan reduced Ang II and NF-kappaB staining and increased eNOS expression, it did not restore HIF-1 alpha expression and did not prevent inflammation. Conversely, tempol increased eNOS and natriuresis, restored HIF-1 alpha expression, and prevented inflammation. Early inflammatory markers observed in rats with acute sodium overload is associated with the imbalance between HIF-1 alpha and eNOS expression. While both losartan and tempol increased natriuresis and eNOS expression, only tempol was effective in restoring HIF-1 alpha expression and down-regulating TGF-beta1 and RANTES expression. The protective role of tempol, but not of losartan, in the inflammatory response may be associated with its greater antioxidant effects., ((c) 2010 Wiley-Liss, Inc.)

Tetrahydrocurcumin is an antioxidative substance, which is derived from curcumin, the component of turmeric. In the present investigation, the effect of tetrahydrocurcumin and curcumin against chloroquine-induced nephrotoxicity were studied in female wistar rats. Oral administration of tetrahydrocurcumin significantly prevented the occurrence of chloroquine (970 mg/kg body weight)-induced renal damage. Upon administration of tetrahydrocurcumin to chloroquine-treated rats, the level of lipid peroxidation was significantly decreased while the levels of non-enzymic and enzymic antioxidants were significantly increased in kidney. Oral administration (80 mg/kg body weight) attenuated the chloroquine-induced nephrotoxicity by significantly decreased levels of serum urea and creatinine with significant normalization of creatinine clearance. On administration of tetrahydrocurcumin, the depleted renal antioxidant defense system (enzymatic and non-enzymatic antioxidants) was significantly increased in rats treated with chloroquine. These biochemical observations were supplemented by histopathological examination of kidney section. These results suggest that administration of chloroquine imposes an oxidative stress to renal tissue and that tetrahydrocurcumin protects the oxidative damage associated with chloroquine.

Background: Angiotensin II (Ang II)-induced renal injury is associated with perivascular inflammation, cell proliferation, and increased superoxide production in the vascular wall. We tested whether lipoic acid, an endogenous antioxidant, protects against the Ang II-induced inflammatory response and end-organ damage., Methods: Light microscopy, immunohistochemistry, electrophoretic mobility shift assay, Northern blots, and high-pressure liquid chromatography (HPLC) were used in kidneys from double transgenic rats (dTGR) harboring human renin and angiotensinogen genes and normotensive Sprague Dawley (SD) rats. The effects of lipoic acid supplementation for three weeks were examined in dTGR and SD rats., Results: Lipoic acid effectively prevented Ang II-induced glomerular and vascular damage in the kidneys and completely prevented the development of albuminuria. Ang II-induced leukocyte infiltration and cell proliferation in the kidney were attenuated. The redox-sensitive transcription factors nuclear factor (kappa) B (NF-kappa B) and activator protein-1 (AP-1) in the kidneys were increased in dTGR compared with SD, and were effectively reduced. Renal glutathione levels were much higher in dTGR than in SD, while the opposite was true for cysteine levels. These results suggested increased renal glutathione oxidation in dTGR, leading to cysteine shortage. Lipoic acid partly prevented renal cysteine depletion and increased hepatic cysteine and glutathione concentrations. This effect was accompanied by increased hepatic gamma-glutamylcysteine synthetase mRNA expression., Conclusion: Our in vivo results suggest that lipoic acid protects against Ang II-induced renal injury through anti-inflammatory/antioxidative mechanisms. The effects are associated with decreased NF-kappa B and AP-1 activation, as well as improved thiol homeostasis.

We previously reported increased monocyte/macrophage infiltration, reactive oxygen species accumulation, and nuclear factor-kappaB (NF-kappaB) activation in mineralocorticoid (deoxycorticosterone acetate [DOCA]) hypertensive rats. We tested the hypothesis that prolonged antioxidant administration inhibits superoxide accumulation, lowers blood pressure, and reduces NF-kappaB activation in DOCA-salt hypertensive rats. DOCA rats exhibited a significant increase in systolic blood pressure compared with sham rats. Aortic rings from DOCA rats exhibited increased superoxide (O(2)(-)) production compared with sham rats. In addition, the treatment of DOCA rats with pyrrolidinedithiocarbamate (PDTC) or 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (Tempol) caused a significant decrease in systolic blood pressure and aortic superoxide accumulation. Monocyte/macrophage infiltration was also significantly decreased in DOCA rats treated with PDTC or Tempol compared with untreated DOCA rats. NF-kappaB-binding activity was significantly greater in untreated DOCA rats than in either sham rats or PDTC- or Tempol-treated DOCA rats. Also, DOCA rats treated with Tempol exhibited no significant difference in NF-kappaB-binding activity compared with sham. These results suggest that antioxidants attenuate systolic blood pressure, suppress renal NF-kappaB-binding activity, and partly alleviate renal monocyte/macrophage infiltration in DOCA-salt hypertension.

Recent research has indicated the role of reactive oxygen species (ROS) in experimental nephritis. We examined the role of ROS and the effect of probucol, an anti-hyperlipidemic drug with antioxidant activity, on adriamycin (ADR)-induced nephrosis in the rat. Fourteen days after single intravenous injection of ADR (7.5 mg/kg b.w.), a nephrotic state was observed. Compared with the normal control values, the total kidney glutathione content was lower on day 5, but significantly higher on day 14 in the ADR-injected rats. Feeding ADR-injected rats with food containing 1% probucol was effective in reducing urinary protein excretion. Serum lipid peroxide level and kidney total glutathione content, both of which increased on day 14 in the ADR-injected rats, were also decreased significantly by concomitant probucol treatment. During long-term observation period of 18 weeks, probucol treatment relieved both urinary protein excretion and the progression of renal impairment. These protective effects of probucol suggest a role of ROS in the induction and progression of ADR nephrosis.