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Introduction: Obesity is a progressive chronic disease that is a renal risk factor. Renal hyperfiltration is an early stage in the development of chronic kidney disease (CKD). The objective of our study is to determine the prevalence of glomerular hyperfiltration in obese patients. Materials and Methods: This is a prospective and descriptive study conducted over a period of 4 months. All patients with BMI over 30 kg/m2 who do not have diabetes, hypertension or another apparent cause of CKD. Results: A total of 85 patients were included, the mean age was 41.96 years, with a female majority. The mean BMI was 38.24kg/m2 and the mean abdominal waist circumference was 114.57cm. Obesity was common in 55.88% and secondary in 44.11%. The prevalence of glomerular hyperfiltration was 85.18% by Cockcroft formula and 48.33% by MDRD formula. Discussion: Obesity is a risk factor for CKD, which promotes increased renal blood flow by vasodilation of the afferent glomerular arteriole, resulting in glomerular hyperfiltration that leads to a change in the glomerular barrier, increasing the risk of developing CKD. According to several studies, the Cockcroft formula is a better predictor of renal function in obese patients. A 51% increase in GFR in obese patients has been observed. In our study, the prevalence of glomerular hyperfiltration is 85.18% according to the Cockcroft formula. Conclusion: Obesity is a risk factor for CKD that needs to be carefully considered.&nbsp

The potential protective effects of mesenchymal stem cells (MSCs) on some kidney diseases have been reported. However, the effect of the fetal kidney–derived (FKD)MSCs on doxorubicin-induced nephropathy has not been studied yet. This study aimed to treat rats with doxorubicin-induced kidney injuries by transplantation of –FKD-MSCs. Twenty-four Sprague-Dawley rats were divided into three groups as control, doxorubicin nephropathy (Sham), and doxorubicin + MSC treated group. Serum biochemistry analysis was performed at the beginning and the end of the study. Functional changes in kidneys were evaluated by scintigraphy. In the doxorubicin nephropathy group, histopathological findings such as mesangial cell proliferation, tubular cast, and glomerular hypertrophy were observed, whereas in the MSC group these findings were significantly reduced. CD133 and CD24 positive immunoreactions were the most severe and frequently observed in the MSC group. While positive staining was detected in the tubular epithelium, there was no immunostaining observed in the glomerulus. The results showed that both functional and histological improvements were achieved in the MSC group compared to the Sham group. In conclusion, transplantation of fetal kidney - derived MSCs into patients with renal damage is thought to contribute to the healing of the renal tissue., Mezenkimal kök hücrelerin (MKH) bazı böbrek hastalıklarındaki potansiyel koruyucu etkileri bildirilmiştir. Bununla birlikte, fetal böbrek kaynaklı MKH'ların doksorubisin ile indüklenmiş nefropati üzerindeki etkisi henüz araştırılmamıştır. Bu çalışmanın amacı, doksorubisin kaynaklı böbrek hasarı olan ratlara fetal böbrek kaynaklı MKH'ların transplantasyonu yapılarak tedavi edilmesidir. Çalışmada yirmi dört adet Sprague – Dawley ırkı rat üç gruba ayrılmıştır. Bunlar: kontrol grubu, doksorubisin nefropatisi (Sham) grubu ve doksorubisin + MKH ile tedavi edilen gruptur. Çalışmanın başında ve sonunda ratlardan kan alınarak serum biyokimya çalışılmıştır. Böbreklerdeki fonksiyonel değişiklikler sintigrafi ile değerlendirilmiştir. Doksorubisin nefropatisi grubunda mezanjiyal hücre proliferasyonu, tübüler alçı ve glomerüler hipertrofi gibi histopatolojik bulgular gözlenirken, MKH grubunda bu bulgular anlamlı olarak azalmıştır. CD133 ve CD24 pozitif immünreaksiyonlar, en şiddetli ve en sık olarak MKH grubunda gözlenmiştir. Tübüler epitelde pozitif boyanma tespit edilirken glomerulusta immün boyanma gözlenmemiştir. Sonuçlar, Sham grubuna kıyasla MKH grubunda hem fonksiyonel hem de histolojik iyileşmelerin sağlandığını göstermiştir. Sonuç olarak, böbrek hasarı olan hastalara fetal böbrek kaynaklı MKH transplantasyonunun böbrek dokusunun iyileşmesine katkıda bulunduğu düşünülmektedir.

Contains fulltext : 234060.pdf (Publisher’s version ) (Open Access) Prematurity and perinatal stress, such as intrauterine growth restriction (IUGR) and chorioamnionitis, are pathological processes creating an impaired intrauterine environment. These intrauterine factors are associated with the development of proteinuria, hypertension, and chronic kidney disease (CKD) later in life. Initially, this was thought to be secondary to oligonephropathy, subsequent glomerular hypertrophy, and hyperfiltration, leading to glomerulosclerosis, a further decrease in nephron number, and finally CKD. Nowadays, there is increasing evidence that prematurity and perinatal stress affect not only nephron endowment but also the maturation of podocytes and vasculogenesis. IUGR is associated with podocyte damage and an aggravated course of nephrotic syndrome. Moreover, preterm birth and IUGR are known to cause upregulation of the postnatal renin-angiotensin system, resulting in hypertension. Chorioamnionitis causes damage to the glomeruli, thereby predisposing to the development of glomerulosclerosis. This review aims to summarize current knowledge on the influence of prematurity, IUGR, and chorioamnionitis on the development of different glomerular structures. After summarizing human and experimental data on low nephron number in general, a specific focus on the current understanding of podocyte and glomerular capillary formation in relation to prematurity and different causes of perinatal stress is presented.

The rising prevalence of obesity-related glomerulopathy (ORG) occurs in accordance with the rising prevalence of obesity worldwide. Clinically ORG is manifested by slowly progressing microalbuminuria that may develop to clinically evident proteinuria. Pathological characteristics of ORG include glomerular hypertrophy in the presence or absence of focal segmental glomerulosclerosis (FSGS). ORG can develop into clinically overt chronic renal insufficiency or even end-stage kidney disease. This article reviews the most important mechanisms for the development of ORG; that are abnormal renal hemodynamics, stimulation of renin-angiotensin-aldosterone system (RAAS), impairment of insulin sensetivity, ectopic lipid deposition, adipose tissue cytokine disorder and local renal micro-inflammation.

Background: Traditional medicine is increasingly favored by the community as an effort to maintain and treat health because it has low side effects and is easy to obtain. Low side effects in administering traditional medicines if the dosage is right, so it is necessary to do an acute toxicity test. One of the consumers of traditional medicine is diabetes mellitus (DM) sufferer. DM can cause delay wound healing. Toman fish is proven to accelerate wound healing. DM sufferers need special attention to their kidneys because in addition to the toxic effects caused by improper doses of traditional medicine, the kidneys can also experience diabetic nephropathy. Objectives: To analyze changes in glomerular hypertrophy and hydropic degeneration in the administration of 16 mL / KgBW Toman fish extract orally for 14 days in diabetic wistar rat kidneys. Methods: This study was a true experimental design with a post test only with control group design. The study was divided into a treatment group of toman fish extract at a dose of 16 mL / Kg BW orally for 14 days in diabetic rat kidney models and a control group in the form of feeding only. Results: The administration of toman fish extract in DM rat showed changes in the glomerular hypertrophy picture of 25-50% and decreased glomerular hypertrophy score which was significantly different from the control group. There was no feature of hydropic degeneration in either group. Conclusions: Giving toman fish extract to DM rat can reduce glomerular hypertrophy and does not cause hydropic degeneration

Objective: To observe the nephroprotective role of berberis vulgar is on renal parenchyma against microscopic and morphometric changes induced by Gentamicin in albino rats. Study Design: Lab based experimental study. Place and Duration of Study: It was conducted in Baqai Medical University in collaboration with department of Anatomy Liaquat National Hospital and Medical College, from Jan to Jul 2017. Methodology: A total of 40 male adult albino rats were used in the study. Four groups were made. Each group contained 10 rats. Group A was a control group, group B received only berberis vulgaris fruit extract orally per day for 21 days, group C received Gentamicin 100 mg/kg/day intraperitonially daily for 21 days. Group D received Gentamicin 100 mg/kg/day intraperitonially along with berberis vulgaris fruit extract 100 mg/kg/day orally. Both kidneys were removed. H&E and PAS stains were used for observing histological alterations and protective role of berberis vulgaris fruit extract. Results: Glomerulus and proximal convoluted tubules were observed histologically in all 4 groups. Microscopy of group B showed parameters nearly similar to control group. Microscopy of group C showed significant derangement in all parameters when compared with control group. Group C showed decrease glomerular, proximal convoluted tubular count was noted. Glomerular diameter increases and there was glomerular hypertrophy and tubular necrosis. Microscopy of group D showed significant improvement due to berberis vulgaris which restored normal renal architecture. Conclusion: Berberis vulgaris has a nephroprotective effect and it can be used as a new medicine against nephrotoxic drugs like Gentamicin.

Kidney aging is a normal physiological process associates with various molecular, morphologic and functional changes in the kidney tissues. This work was designed to study microscopically the structural changes in the kidney tissue of aged rats compared to young rats. Male Sprague–Dawley rats were used 10 young rats (4 months) and 10 aged rats (24 months). Rats were transcardially perfused with 4% paraformaldehyde. The kidneys were post fixed for 24 hours in 4 % PFA then proceeded for normal histopathology and light microscopic examination. Kidney tissue of aged rats showed serious morphological changes such as; segmental glomerulosclerosis, pericapsular fibrosis, tubulointerstitial fibrosis, perivascular fibrosis, inflammatory cell infiltration, tubular dilatation, intra-tubular cast formation and tubular atrophy. These changes were compared to the normal histological appearance of glomeruli, tubules, interstitium, blood vessels of young rat kidneys. In addition, the kidney tissue of the aged rats showed compensatory glomerular hypertrophy, tubular hyperplasia and endothelial proliferation. Renal aging involves several degenerative changes in kidney structure and these alterations interfere with the physiologic functions and end with chronic renal failure.

Background Previously, by using proteomic analysis and RNA sequencing in isolated glomeruli, we identified several novel differentially expressed proteins in human and mouse diabetic nephropathy (DN) versus controls, including dishevelled associated activator of morphogenesis 2 (DAAM2). DAAM2 binds the Wnt effector Dvl. We aimed to study possible contributions of DAAM2 to DN. Methods We assessed DAAM2 by immunostaining in non-cancer regions of human nephrectomy (Nx), DN and normal donor kidney tissues. We also examined DAAM2 in DN mice (db/db eNOS−/−) and Nx mice. DN mice treated with angiotensin-converting enzyme inhibitor (ACEI), dipeptidyl peptidase 4 inhibitor (DPP4I) or vehicle were compared. DAAM2 was knocked down in primary cultured podocytes by small interfering RNA to study its effects on cell function. Results In normal human glomeruli, DAAM2 was expressed only on podocytes. DAAM2 expression was increased in both Nx and DN versus normal donors. Podocyte DAAM2 expression was increased in DN and Nx mouse models. Glomerular DAAM2 expression correlated with glomerular size and was decreased significantly by ACEI while DPP4I only numerically reduced DAAM2. In primary cultured podocytes, knockdown of DAAM2 enhanced adhesion, slowed migration, activated Wnt–β-catenin signaling and downregulated mammalian target of rapamycin complex 1 (mTORC1) and Rho activity. Conclusions Podocyte DAAM2 is upregulated in both Nx and DN, which could be contributed to by glomerular hypertrophy. We hypothesize that DAAM2 regulates podocyte function through the mTORC1, Wnt/β-catenin and Rho signaling pathways.

Cyanotic congenital heart disease is occasionally associated with kidney dysfunction, which is known as cyanotic nephropathy or cyanotic glomerulopathy. The clinical presentation of cyanotic nephropathy includes proteinuria, decreased estimated glomerular filtration rate, hyperuricemia, thrombocytopenia, or polycythemia. Although advances in surgical procedures have improved the prognosis of cyanotic congenital heart diseases, adult cases of cyanotic nephropathy are still rare, and there are few reports of kidney biopsy in adults with cyanotic nephropathy. Here, we present the case of a 41-year-old patient with Fontan palliation who developed nephrotic range proteinuria and had a kidney biopsy, which showed glomerular hypertrophy with segmental glomerulosclerosis around vascular poles, suggesting adaptive focal segmental glomerulosclerosis. This case provides further understanding of kidney dysfunction due to cyanotic congenital heart disease and shows the need for attention in the management for prevention of progression to end-stage renal disease and in the selection of renal replacement therapy.

Acute kidney injury (AKI) increases the risk for chronic kidney disease (CKD). However, there are few tools to detect microstructural changes after AKI. Here, cationic ferritin-enhanced magnetic resonance imaging (CFE-MRI) was applied to examine the heterogeneity of kidney pathology in the transition from AKI to CKD. Adult male mice received folic acid followed by cationic ferritin and were euthanized at four days (AKI), four weeks (CKD-4) or 12 weeks (CKD-12). Kidneys were examined by histologic methods and CFE-MRI. In the CKD-4 and CKD-12 groups, glomerular number was reduced and atubular cortical lesions were observed. Apparent glomerular volume was larger in the AKI, CKD-4 and CKD-12 groups compared to controls. Glomerular hypertrophy occurred with ageing. Interglomerular distance and glomerular density were combined with other MRI metrics to distinguish the AKI and CKD groups from controls. Despite significant heterogeneity, the noninvasive (MRI-based) metrics were as accurate as invasive (histological) metrics at distinguishing AKI and CKD from controls. To assess the toxicity of cationic ferritin in a CKD model, CKD-4 mice received cationic ferritin and were examined one week later. The CKD-4 groups with and without cationic ferritin were similar, except the iron content of the kidney, liver, and spleen was greater in the CKD-4 plus cationic ferritin group. Thus, our study demonstrates the accuracy and safety of CFE-MRI to detect whole kidney pathology allowing for the development of novel biomarkers of kidney disease and providing a foundation for future in vivo longitudinal studies in mouse models of AKI and CKD to track nephron fate.

Diabetic nephropathy (DN) is the most serious end-stage renal disease which characterized by renal glomerular sclerosis including glomerular hypertrophy, glomerular basement membrane (GBM) thickening, mesangial expansion and renal fibrosis. TGF-β/Smads signal pathway plays a crucial role in the development of renal fibrosis. In this study, we found that GdCl3 which was an agonist of Calcium-sensing receptor (CaSR) could repress the activation of TGF-β/Smads signal pathway induced by TGF-β1 or high glucose and then alleviated the accumulation of extracellular matrix (ECM) in mesangial cells and the kidney of type1 diabetic rats. Further study indicated that GdCl3 could induce the binding of CaSR and TβR II and then both of these two receptors translocated from cell membrane to cytoplasm, in this case, TβR II on the cell membrane was decreased and then desensitized to the stimulation of its ligand TGF-β1, so that the activation of its downstream factors such as Smad2 and Smad3 were blocked, finally, ECM expression in mesangial cells were inhibited. We concluded that GdCl3 could alleviate the accumulation of ECM in mesangial cells via antagonizing TGF-β/Smads signal pathway in diabetes mellitus. ispartof: Journal of Pharmacological Sciences vol:142 issue:2 pages:41-49 ispartof: location:Japan status: published

Glomerular tuft immune reactive Ezrin surface area (EzA) and fraction of EzA to total glomerular tuft area significantly increased, indicating podocyte growth, rounding and altered cytoskeletal interactions at 1 week of STZ diabetes. Podocyte number per glomerulus (WT1+ nuclei) did not change indicating no detachment, but density decreased due to tuft hypertrophy. Treatment with PLZ or Insulin for one week, prevented increase in proteinuria and hyperglycemia but not the decrease in podocyte density. PLZ but not Insulin prevented increase in ezrin positive area in glomeruli and per podocyte. In podocytes in culture neither 25 mM glucose with or without PLZ (2.5 or 25 uM) altered Ezrin expression measured in western blots. In summary, the Ezrin positive glomerular surface area increase seen after 1 week of STZ diabetes, reflects altered podocyte morphology and cytoskeletal interactions, prevented by PLZ but not by insulin. Ezrin area increase preceded podocyte detachment and in podocytes in culture is not associated with increases in podocyte Ezrin protein expression. It is a likely precursor of shape changes in podocytes and of alterd interactions with basement membrane that contribute to detachment and thickening. Glomerular capillary tuft hypertrophy and reduced podocyte density persisted despite PLZ or insulin treatments, independently of levels of glycemia and of proteinuria.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease. The natural history of DKD includes glomerular hyperfiltration, progressive albuminuria, declining estimated glomerular filtration rate, and, ultimately, kidney failure. It is known that DKD is associated with metabolic changes caused by hyperglycemia, resulting in glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Hyperglycemia is also known to cause programmed epigenetic modification. However, the detailed mechanisms involved in the onset and progression of DKD remain elusive. In this review, we discuss recent advances regarding the pathogenic mechanisms involved in DKD.

Background: Podocyte foot process effacement is a key histologic finding in proteinuric kidney disease. We previously showed that 3-week old CD2AP-deficient mice have significant proteinuria, glomerular hypertrophy and mesangial expansion. The goal of this study is to use morphometry to establish the temporal sequence of podocyte foot process effacement, glomerular volume expansion and albuminuria in Cd2ap−/− mice by measuring these parameters at the 2-week time point.Methods: Wild-type mice age 14 ± 1 days with the Cd2ap gene (WT, N = 5) and mice deficient for Cd2ap (Cd2ap KO, N = 5) were generated. Kidneys were harvested and fixed in 2.5% glutaraldehyde and processed for examination by light and electron microscopy. An average of 415.2 (range 268–716) grid points were counted for all the glomeruli, and quantification of glomerular volume from each kidney. Urine was collected the day prior to sacrifice for urine albumin-to-creatinine ratio (ACR) measurements.Results: There was no difference in albuminuria [median (range) mg/g] between WT [212.2 (177.6–388.4) mg/g] vs. Cd2ap KO mice [203.3 (164.7–910.2) mg/g], P = 0.89; or glomerular volume 68,307[10,931] vs. 66,844[13,022] μm3, p = 0.92. The volume densities of glomerular components of the podocyte, capillary lumen and mesangium were not different for the two groups, P = 0.14, 0.14 and 0.17 respectively. However, foot process width was increased in Cd2ap KO 1128[286] vs. WT [374 ± 42] nm, P = 0.02.Conclusion: Here we show that while 2-week old WT and Cd2ap KO mice have similar levels of albuminuria, glomerular and mesangial volume, Cd2ap KO mice have more extensive podocyte foot process effacement. The data suggests that podocyte injury is the initiating event leading to mesangial expansion and albuminuria in this model.

Aims/hypothesis Chronic low-grade inflammation with local upregulation of proinflammatory molecules plays a role in the progression of obesity-related renal injury. Reduced serum concentration of anti-inflammatory adiponectin may promote chronic inflammation. Here, we investigated the potential anti-inflammatory and renoprotective effects and mechanisms of action of AdipoRon, an adiponectin receptor agonist. Methods Wild-type DBA/2J mice were fed with high-fat diet (HFD) supplemented or not with AdipoRon to model obesity-induced metabolic endotoxaemia and chronic low-grade inflammation and we assessed changes in the glomerular morphology and expression of proinflammatory markers. We also treated human glomeruli ex vivo and human podocytes in vitro with AdipoRon and bacterial lipopolysaccharide (LPS), an endotoxin upregulated in obesity and diabetes, and analysed the secretion of inflammatory cytokines, activation of inflammatory signal transduction pathways, apoptosis and migration. Results In HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-κB p65 subunit (NF-κB-p65) (70%, p p p p p p p p p p p p p Conclusions/interpretation AdipoRon attenuated the renal expression of proinflammatory cytokines in HFD-fed mice and LPS-stimulated human glomeruli, which apparently contributed to the amelioration of glomerular inflammation and injury. Mechanistically, based on assays on cultured podocytes, AdipoRon reduced LPS-induced activation of the NF-κB-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNFα. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation. Graphical abstract

Anti-inflammatory and antidiabetogenic properties have been ascribed to cannabidiol (CBD). CBD-based medicinal drugs have been approved for over a lustrum, and a boom in the commercialization of CBD products started in parallel. Herein, we explored the efficacy of CBD in streptozotocin (STZ)-induced diabetic mice to prevent diabetic nephropathy at onset. Eight-to-ten-week-old C57BL6J male mice were treated daily intraperitoneally with 10 mg/kg of CBD or vehicle for 14 days. After 8 days of treatment, mice were challenged with STZ or vehicle (healthy-control). At the end of the study, non-fasting blood glucose (FBG) level was 276 ± 42 mg/dL in vehicle-STZ-treated compared to 147 ± 9 mg/dL (p ≤ 0.01) in healthy-control mice. FBG was 114 ± 8 mg/dL in vehicle-STZ-treated compared to 89 ± 4 mg/dL in healthy-control mice (p ≤ 0.05). CBD treatment did not prevent STZ-induced hyperglycemia, and non-FBG and FBG levels were 341 ± 40 and 133 ± 26 mg/dL, respectively. Additionally, treatment with CBD did not avert STZ-induced glucose intolerance or pancreatic beta cell mass loss compared to vehicle-STZ-treated mice. Anatomopathological examination showed that kidneys from vehicle-STZ-treated mice had a 35% increase of glomerular size compared to healthy-control mice (p ≤ 0.001) and presented lesions with a 43% increase in fibrosis and T cell infiltration (p ≤ 0.001). Although treatment with CBD prevented glomerular hypertrophy and reduced T cell infiltration, it significantly worsened overall renal damage (p ≤ 0.05 compared to vehicle-STZ mice), leading to a more severe renal dysfunction than STZ alone. In conclusion, we showed that CBD could be detrimental for patients with type 1 diabetes, particularly those undergoing complications such as diabetic nephropathy.

Increasing evidence suggests that single in kidney states (e.g., kidney transplantation and living donation) progressive glomerulosclerosis limits kidney lifespan. Modeling shows that post-nephrectomy compensatory glomerular volume (GV) increase drives podocyte depletion and hypertrophic stress resulting in proteinuria and glomerulosclerosis, implying that GV increase could serve as a therapeutic target to prevent progression. In this report we examine how Angiotensin Converting Enzyme inhibition (ACEi), started before uninephrectomy can reduce compensatory GV increase in wild-type Fischer344 rats. An unbiased computer-assisted method was used for morphometric analysis. Urine Insulin-like growth factor-1 (IGF-1), the major diver of body and kidney growth, was used as a readout. In long-term (40-week) studies of uni-nephrectomized versus sham-nephrectomized rats a 2.2-fold increase in GV was associated with reduced podocyte density, increased proteinuria and glomerulosclerosis. Compensatory GV increase was largely prevented by ACEi started a week before but not after uni-nephrectomy with no measurable impact on long-term eGFR. Similarly, in short-term (14-day) studies, ACEi started a week before uni-nephrectomy reduced both GV increase and urine IGF-1 excretion. Thus, timing of ACEi in relation to uni-nephrectomy had significant impact on post-nephrectomy “compensatory” glomerular growth and outcomes that could potentially be used to improve kidney transplantation and live kidney donation outcomes.

Most of the obesity murine models inducing renal injury use calorie‐enriched foods, where fat represents 60% of the total caloric supply, however, this strategy doubles the standard proportion of fat ingestion in obese patients. Therefore, it is crucial to study the impact of a high‐fat intake on kidney physiology that resembles common obesity in humans to understand the trigger mechanisms of the long‐term consequences of overweight and obesity. In this study, we analyzed whether chronic feeding with a moderately high fat diet (MHFD) representing 45% of total calories, may induce kidney function and structural injury compared to C57BL/6 mice fed a control diet. After 14 weeks, MHFD induced significant mice obesity. At the functional level, obese mice showed signs of kidney injury characterized by increased albuminuria/creatinine ratio and higher excretion of urinary biomarkers of kidney damage. While, at the structural level, glomerular hypertrophy was observed. Although, we did not detect renal fibrosis, the obese mice exhibited a significant elevation of Tgfb1 mRNA levels. Kidney damage caused by the exposure to MHFD was associated with greater oxidative stress, renal inflammation, higher endoplasmic reticulum (ER)‐stress, and disruption of mitochondrial dynamics. In summary, our data demonstrate that obesity induced by a milder fat content diet is enough to establish renal injury, where oxidative stress, inflammation, ER‐stress, and mitochondrial damage take relevance, pointing out the importance of opportune interventions to avoid the long‐term consequences associated with obesity and metabolic syndrome., Here, we demonstrated that obesity induced by a MHFD is enough to establish kidney damage, where oxidative stress, renal inflammation, ER‐stress, and mitochondrial damage take relevance, pointing out the importance of opportune interventions to avoid the long‐term consequences associated with obesity.

Simple Summary The worldwide prevalence of diabetes mellitus (DM) in 2020 has been estimated at 463 million patients. About 90% of patients with diabetes have type 2 diabetes mellitus (T2D), caused primarily by insulin resistance and insufficiency. However, the specific etiology of T2D remains unknown. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a novel class of anti-diabetic drugs that act independently of insulin and reduce blood glucose concentrations by inhibiting the reabsorption of glucose at renal proximal tubules. SGLT2 inhibitors have highlighted the role of the kidneys in glycemic control in diabetes. The kidneys have multiple roles in systemic glucose metabolism, such as glucose reabsorption, gluconeogenesis, and insulin degradation. Therefore, putative renal hyperfunction might contribute to the development of T2D. The present study characterized rats from a strain of novel type 2 diabetes model with enlarged kidneys (DEK). Their kidneys have increased parenchyma (nephrons and tubules), and uninephrectomy immediately after the onset inhibited the development of T2D for a significant period in DEK rats. These results highlight the contribution of kidney to the development of T2D, and indicate that the kidneys are therapeutic targets to prevent T2D. Abstract The kidneys participate in the regulation of systemic glucose metabolism via gluconeogenesis, insulin degradation, and the tubular reabsorption of glucose. The present study characterized rats from a strain of a novel type 2 diabetes model with enlarged kidneys (DEK). Histological and biochemical analyses of DEK rats were performed to assess the relationships between their kidneys and hyperglycemia. The kidney weight of diabetic DEK (DEK-DM) gradually increased over time from the onset of diabetes, with the glomerular number being higher in DEK-DM than in normal DEK (DEK-cont). A positive correlation between blood glucose level and kidney weight was observed in DEK-DM. The similar glomerular size and single glomerular creatinine clearance in DEK-cont and DEK-DM indicated that glomerular hypertrophy and hyperfiltration were not involved in the renal enlargement. Uninephrectomy (1/2Nx) in DEK-DM resulted in a reduction in blood glucose level at 7–28 post-operation days, with this concentration remaining lower than in Sham group until 84 days post-operation. 1/2Nx also improved systemic conditions, including reduced body weight gain, polyuria, polydipsia, and hyperphagia. Plasma concentrations of Na, total cholesterol, albumin, and total protein were higher, and urinary excretion of glucose, urea nitrogen, and proteins were lower, in the 1/2Nx than in the Sham group. Remnant kidney weight was two-fold higher in the 1/2Nx than in the Sham group 84 days later. In addition, 1/2Nx resulted in renal tubular dilatation but not in the progression of fibrosis or glomerular lesions. Taken together, these findings indicate that enlarged kidneys were associated with the onset of diabetes and with the resistance to diabetic nephropathy in DEK-DM.

Introduction: Emerging treatments of diabetic kidney disease (DKD) include SGLT2 inhibitors and GLP-1 receptor agonists that are nephroprotective beyond their blood glucose lowering effects. To confirm the translatability of a mouse model for drug discovery in DKD, we tested the efficacy of an ACE inhibitor and a SGLT2 inhibitor in the reninAAV UNx db/db mouse model. Methods: Female db/db mice were injected with a renin-encoding adeno-associated virus construct (reninAAV) to induce hypertension and uninephrectomized (UNx). At 12 weeks of age, dosing with vehicle, lisinopril, empagliflozin, or the combination (combo) was initiated. Plasma and urine markers were measured after 12 weeks of dosing and terminal kidney samples were collected for 3D light sheet microscopy and 2D histology. Results: In reninAAV UNx db/db mice, treatment with empagliflozin and combo reduced fed BG and HbA1c compared to vehicle. Treatment with lisinopril and combo reduced urine ACR and KIM1-to-creatinine compared to vehicle, while treatment with empagliflozin alone worsened urine ACR. Glomerular hypertrophy as assessed by 3D imaging was reduced in combo treated reninAAV UNx db/db mice compared to vehicle, while treatment with empagliflozin alone worsened glomerular hypertrophy. The total number of glomeruli per kidney was unaffected by treatments. Compared to vehicle treatment, lisinopril and combo treatment reduced the fraction of score 3+4 glomeruli, and glomerulosclerosis index (GSI) was reduced by with lisinopril and combo treatment. Treatment with empagliflozin alone worsened GSI. Morphometric analyses showed that lisinopril and combo treatment reduced kidney CD11b and KIM1 load. Conclusion: Responses to the combination treatment with lisinopril and empagliflozin showed improvement of urine and histological markers of DKD. Together, these data confirm the translatability of the reninAAV UNx db/db mouse model of DKD. Disclosure M. V. Østergaard: None. M. Christensen: None. T. Secher: Employee; Self; Gubra, Employee; Spouse/Partner; Novo Nordisk, Stock/Shareholder; Self; Gubra, Stock/Shareholder; Spouse/Partner; Novo Nordisk. J. L. Skytte: None. U. Roostalu: Employee; Self; Gubra. C. G. Salinas: Employee; Self; Gubra, Employee; Spouse/Partner; Novo Nordisk, Stock/Shareholder; Spouse/Partner; Novo Nordisk. F. E. Sembach: None. L. N. Fink: Employee; Self; Gubra, Stock/Shareholder; Self; Novo Nordisk A/S. N. Vrang: Board Member; Self; Gubra, Employee; Self; Gubra, Stock/Shareholder; Self; Gubra.

Background: Diabetic Kidney Disease (DKD) is a common complication of diabetes and a leading cause of end-stage renal disease progression. Therefore, therapeutic strategies are desirable to mitigate the progression of disease into more severe consequences. Hypothesis/Purpose: Tinospora cordifolia is a traditionally known antidiabetic plant; however, its effect against DKD remains unexplored. Therefore, in the present study, we assessed the efficacy and mechanism of action of Tinospora cordifolia extract (TC) against DKD. Methods: The molecular interaction of the various phytoconstituents of TC with PPARγ were analyzed in silico. The effect of TC was studied on the viability, cell cycle, and gene expressions (PPARγ, TGFβ, and αSMA) in high glucose treated NRK-52E and SV40 MES13 cells. Further, streptozotocin-induced diabetic rats were treated with TC for eight weeks, and the effects on different biochemical, histological and molecular parameters were studied. Results: In silico analysis revealed the integration of various phytoconstituents of TC with PPARγ. It further increased PPARγ and decreased TGFβ and αSMA expressions in NRK-52E and SV40 MES13 cells. In diabetic rats, TC improved the fasting blood glucose, serum urea, and creatinine levels. It also lowered the urine microalbumin and advanced glycation end products (AGEs) levels. Histopathological studies revealed the preventive effect of TC on degenerative changes, mesangial proliferation and glomerular hypertrophy. Further, it reduced the inflammation and fibrotic changes in the kidney tissue estimated by various markers. The kidney tissue and gene expression analysis revealed the augmented levels of PPARγ after TC treatment. Conclusion: In conclusion, TC exerted the protective effect against DKD by inhibiting inflammation and fibrogenesis through the activation of PPARγ dependent pathways.

(1) Background: Diabetic nephropathy (DN) is common complication of diabetes. Current therapy for DN does not include promotion of podocyte protection. Therefore, we investigated the therapeutic effect of melatonin (Mel) combined extracorporeal shock wave (SW) therapy on a DN rat model. (2) Methods: The DN rats were treated with Mel (5 mg/kg) twice a week for 6 weeks and SW treatment once a week (0.13 mJ/mm2) for 6 weeks. We assessed urine microalbumin, albumin to creatinine ratio (ACR), glomerular hypertrophy, glomerular fibrosis, podocyte markers (Wilm’s tumor protein-1, synaptopodin and nephrin), cell proliferation, cell survival, cell apoptosis, renal inflammation and renal oxidative stress. (3) Results: The Mel combined SW therapy regimen significantly reduced urine microalbumin excretion (3.3 ± 0.5 mg/dL, p &lt, 0.001), ACR (65.2 ± 8.3 mg/g, p &lt, 0.001), glomerular hypertrophy (3.1 ± 0.1 × 106 μm3, p &lt, 0.01) and glomerular fibrosis (0.9 ± 0.4 relative mRNA fold, p &lt, 0.05). Moreover, the Mel combined SW therapy regimen significantly increased podocyte number (44.1 ± 5.0% area of synaptopodin, p &lt, 0.001) in the Mel combined SW group. This is likely primarily because Mel combined with SW therapy significantly reduced renal inflammation (753 ± 46 pg/mg, p &lt, 0.01), renal oxidative stress (0.6 ± 0.04 relative density, p &lt, 0.05), and apoptosis (0.3 ± 0.03 relative density, p &lt, 0.001), and also significantly increased cell proliferation (2.0 ± 0.2% area proliferating cell nuclear antigen (PCNA), p &lt, 0.01), cell survival, and nephrin level (4.2 ± 0.4 ng/mL, p &lt, 0.001). (4) Conclusions: Mel combined SW therapy enhances podocyte protection and ameliorates kidney function in a DN rat model. Mel combined SW therapy may serve as a novel noninvasive and effective treatment of DN.

BACKGROUND AND AIMS Arterial hypertension and glomerular ischemia coexist in elderly patients with hypertension. Thus, 2 conflicting therapeutic purposes, i.e., reduction of pressure overload and maintenance of renal arterial perfusion, must be considered in elderly patients with hypertension. This study examined this issue from the perspective of renal histopathology. METHODS Adult autopsied kidneys without apparent renal disease were analyzed for histopathological features that might be related to aging or hypertension. Mean glomerular volume (GV), global glomerulosclerosis (GGS), arteriosclerotic lesions (AL), arteriolar hyalinosis (AH), and interstitial fibrosis/tubular atrophy (IF/TA) were evaluated. RESULTS This study included 59 Japanese autopsy patients, of whom 28 (47%) were hypertensive. Overall, GGS, IF/TA, and AL, but not GV or AH, tended to increase with aging. Multivariate analysis revealed that age, but not hypertension, was an independent factor associated with GGS, IF/TA, and AL. In contrast, hypertension was independently associated with GV. AH was not associated with age or hypertension in this autopsy series. Of note, in the late elderly group (≥75 years), GGS was significantly lower in hypertensives than in normotensives. No such trend was found in the non-elderly ( CONCLUSIONS Normal aging has a major impact on the development of renal sclerotic lesions compared to hypertension in adults with no apparent renal disease. Hypertension may play a role in maintaining downstream glomerular perfusion in the aging kidney.

In type 2 diabetes mellitus (T2DM), hyperglycemia promotes oxidative stress and eventually leads to diabetic nephropathy (DN). Sporidiobolus pararoseus is reported to exhibit enhanced anti-oxidation properties. However, its role in DN remains obscure. This study aimed to determine the antioxidative effects of a Sporidiobolus pararoseus wall-broken powder (SPP) supplement on DN and investigate the possible underlying mechanisms. A model of T2DM was successfully established, and C57BL/6J male mice were fed a high-fat diet for 4 weeks and then injected with streptozotocin (100 mg per kg per day) for three consecutive days. After eight weeks of intervention, SPP strongly lowered fasting glucose levels, serum creatinine, serum urea nitrogen, urinary albumin and reduced glomerular hypertrophy and mesangial matrix expansion. In addition, SPP increased the activities of SOD, T-AOC, CAT, and GST and decreased the amount of MDA. Furthermore, it was revealed that SPP significantly abrogated oxidative stress not only by activating the Nrf2 gene but also by activating two Nrf2-targeted antioxidative genes (NQO-1 and HO-1) compared with metformin hydrochloride, which is widely accepted as a diabetes drug. Our study showed that SPP has antioxidant properties and delays the progression of DN; the underlying mechanism may be associated with activation of the Nrf2/ARE pathway.

Background: Glomerular hyperfiltration (GH) is a hallmark of renal dysfunction in diabetes and obesity. Recent clinical trials demonstrated that SGLT2 inhibitors are renoprotective, possibly by abating hyperfiltration. The present review considers the current evidence for a cause-to-effect relationship between hyperfiltration-related physical forces and the development of chronic kidney disease (CKD). Summary: Glomerular hyperfiltration is associated with glomerular and tubular hypertrophy. Hyperfiltration is mainly due to an increase in glomerular capillary pressure, which increases tensile stress applied to the capillary wall structures. In addition, the increased ultrafiltrate flow into Bowman’s space heightens shear stress on the podocyte foot processes and body surface. These mechanical stresses lead to an increase in glomerular basement membrane (GBM) length and to podocyte hypertrophy. The ability of the podocyte to grow being limited, a mismatch develops between the GBM area and the GBM area covered by foot processes, leading to podocyte injury, detachment of viable podocytes, adherence of capillaries to parietal epithelium, synechia formation and segmental sclerosis. Mechanical stress is also applied to post-filtration structures, resulting in dilation of glomerular and tubular urinary spaces, increased proximal tubular sodium reabsorption by hypertrophied epithelial cells and activation of mediators leading to tubulointerstitial inflammation, hypoxia and fibrosis Key Messages: GH-related mechanical stress leads to both adaptive and maladaptive glomerular and tubular changes. These flow-related effects play a central role in the pathogenesis of glomerular disease. Attenuation of hyperfiltration is thus an important therapeutic target in diabetes and obesity-induced CKD.

Many preclinically promising therapies for diabetic kidney disease fail to provide efficacy in humans, reflecting limited quantitative translational understanding between rodent models and human disease. To quantitatively bridge interspecies differences, we adapted a mathematical model of renal function from human to mice, and incorporated adaptive and pathological mechanisms of diabetes and nephrectomy to describe experimentally observed changes in glomerular filtration rate (GFR) and proteinuria in db/db and db/db UNX (uninephrectomy) mouse models. Changing a small number of parameters, the model reproduced interspecies differences in renal function. Accounting for glucose and Na+ reabsorption through sodium glucose cotransporter 2 (SGLT2), increasing blood glucose and Na+ intake from normal to db/db levels mathematically reproduced glomerular hyperfiltration observed experimentally in db/db mice. This resulted from increased proximal tubule sodium reabsorption, which elevated glomerular capillary hydrostatic pressure (Pgc) in order to restore sodium balance through increased GFR. Incorporating adaptive and injurious effects of elevated Pgc, we showed that preglomerular arteriole hypertrophy allowed more direct transmission of pressure to the glomerulus with a smaller mean arterial pressure rise; Glomerular hypertrophy allowed a higher GFR for a given Pgc; and Pgc-driven glomerulosclerosis and nephron loss reduced GFR over time, while further increasing Pgc and causing moderate proteinuria, in agreement with experimental data. UNX imposed on diabetes increased Pgc further, causing faster GFR decline and extensive proteinuria, also in agreement with experimental data. The model provides a mechanistic explanation for hyperfiltration and proteinuria progression that will facilitate translation of efficacy for novel therapies from mouse models to human., Mathematical model of mouse diabetic kidney injury Many drugs for diabetic kidney disease appear to work in rodents, but fail in humans, reflecting incomplete understanding of disease processes. A team led by Melissa Hallow at the University of Georgia has developed a mathematical model that explains how elevated blood glucose in diabetes causes kidney injury in mice. They first showed that normal human, rat, or mouse kidney physiology could be reproduced with the same model by changing a small number of parameters. They then showed that diabetes-induced increases in sodium reabsorption cause unintuitive changes in kidney function that increase pressure on glomerular capillaries, causing protein leakage and nephron loss. The model reproduced faster disease progression observed in diabetic mice who have had one kidney removed. This mathematical understanding of diabetic kidney injury may improve translation of novel therapies from mice to human.

CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Os mastócitos apresentam ações antifibróticas e pró-fibróticas e parecem contribuir para o desenvolvimento da nefropatia diabética (ND). Apesar de existirem dados na literatura sobre o papel de alguns mediadores mastocitários na patogênese da ND, pouco é conhecido sobre os mecanismos celulares envolvidos no processo, em especial daqueles relativos à deposição renal de fibras de colágeno do tipo I e III. Assim, avaliamos o efeito do tratamento com cromoglicato dissódico (CR), droga que inibe a desgranulação mastocitária, sobre parâmetros morfofuncionais de rins de animais portadores de diabetes mellitus experimental, induzido pela administração de aloxana (50 mg/kg, i.v.). Animais controles ou diabéticos (glicemia >200 mg/dl) foram tratados ou não com CR (50 mg/kg/dia, i.p., do 7° dias após a indução até o 95° dia). No 90° dia, a excreção urinária de albumina (EUA) e a taxa de filtração glomerular (TFG) foram avaliadas. No 95° dia de experimento, após a aferição da pressão arterial sistólica (PAS), os animais foram anestesiados e eutanasiados para a coleta e processamento dos rins. Secções do tecido renal foram submetidas a análises morfológicas (lâminas coradas com azul de toluidina ou vermelho de picrossírius) ou de imuno-histoquímicas para detecção de α-actina de músculo liso (α-SMA) e antígeno nuclear de proliferação celular (PCNA). O DM aumentou a densidade e atividade mastocitária renal, a área do corpúsculo renal, a área do tufo glomerular, o peso relativo do rim, a deposição renal de fibras de colágeno do tipo III e a soma do colágeno do tipo I com o do tipo III, a EUA, e a expressão de PCNA túbulo-intersticial, mas diminuiu a TFG e não alterou a expressão renal de α-SMA, tão pouco a PAS. O tratamento com CR reverteu parcialmente às alterações observadas na densidade e atividade mastocitária, na área do corpúsculo renal, no peso relativo do rim, na deposição de fibras de colágeno no parênquima renal e na TFG. A área do tufo glomerular e a expressão de PCNA foram normalizadas pelo tratamento com CR, enquanto a EUA, a PAS e a expressão de α-SMA não forma modificadas. Esses dados sugerem que os aumentos na densidade e atividade mastocitárias renais contribuem para a deposição de colágeno túbulo-intersticial nos estágios iniciais da ND, mesmo na ausência de alterações na população renal de miofibroblastos. O tratamento com CR evidenciou efeitos renoprotetores que parecem estar relacionados à sua ação inibitória sobre a desgranulação mastocitária, bem como à sua capacidade de prevenir alterações morfofuncionais deletérias. Mast cells have antifibrotic and pro-fibrotic actions and appear to contribute to the development of diabetic nephropathy (DN). Despite the role of some possible mast cell mediators in the pathogenesis of DN has been proposed, little is known about the cellular mechanisms involved in the process, mainly those concerning type I and III collagen deposition in the renal parenchyma. Therefore, we evaluated the effect of disodium cromoglycate (CG) treatment, a drug that inhibits mast cell degranulation, on the morphofunctional parameters of kidneys from rats with experimental diabetes mellitus (DM) induced by the administration of alloxan (50 mg/kg, i.v.). Control or diabetic animals (blood glucose> 200 mg/dl) were treated or not with CR (50 mg/kg/day, i.p., from the 7th day after DM induction until 95th day). Urinary albumin excretion (UAE) and glomerular filtration rate (GFR) were assessed on the 90th day. After systolic blood pressure (SBP) measurement, kidneys were collected from anesthetized animals on the 95th day. Kidney slides stained with toluidine blue or picrosirius red were subjected to morphological analysis or immunohistochemistry to detect α-smooth muscle actin (α-SMA) or proliferating cell nuclear antigen (PCNA). Renal mast cell density and activity, renal corpuscle and tuft glomerular area, kidney weight/body weight ratio, renal interstitial collagen deposition (type III, and the sum of type I with type III collagen), UAE, and tubulointerstitial PCNA expression were increased in diabetic animals. Despite DM decreased GFR, neither renal α-SMA expression nor SBP were altered by the disease. The alteration in renal mast cell density and activity, renal corpuscle area, kidney weight/body weight ratio, renal interstitial collagen deposition and GFR were partially reversed by CG treatment. Glomerular tuft area and tubulointerstitial PCNA expression were normalized by CG treatment, while UAE, SBP and renal α-SMA expression did not change. These data suggest that the increases in the density and activity of mast cells within the kidney in the early stages of DN contribute to tubulointerstitial collagen deposition even in the absence of alterations in the renal myofibroblast population. CG treatment showed renoprotective effects in diabetic rats which appears to be related to its mast cell stabilizing property and to its ability to prevent some detrimental morphofunctional alterations. Dissertação (Mestrado) 2023-01-29

BackgroundKidney involvement of visceral Leishmaniasis is previously reported, but knowledge is limited. Hypergammaglobulinemia is common in visceral leishmaniasis patients. Whether hypergammaglobulinemia after leishmaniasis depletion can cause kidney injury is not well reported yet.Case presentationWe reported a patient who recovered from visceral Leishmaniasis but showed persistent hypergammaglobulinemia and elevated urinary protein. Kidney biopsy showed glomerular hypertrophy with mild segmental mesangial proliferation without tubulointerstitial involvement in light microscopy. No immune complex deposit was found in the mesangial area by neither immunofluorescent staining nor electronic microscope. Increased lysosomes were observed in proximal tubules by electronic microscope. Valsartan was administered to decrease urinary protein, and no immune-suppressive therapy was added. The urinary protein and serum IgG level gradually dropped, and serum creatinine level remained stable during three- month follow up.ConclusionsHypergammaglobulinemia is unlikely to cause renal structural or functional damage in the short term. Angiotensin blockade significantly reduced urine protein, with a minor effect on IgG elimination.

Glomerular hyperfiltration is observed in an early stage of kidney diseases including diabetic nephropathy. A better understanding of pathophysiological changes in glomerular hyperfiltration is essential for development of new therapies to prevent kidney disease progression. In this study, we investigated glomerular changes including glomerular filtration rate (GFR) and glomerular size in the Spontaneously Diabetic Torii (SDT) fatty rat, an obese type 2 diabetic model, and we also evaluated pharmacological effects of the sodium glucose cotransporter 2 inhibitor dapagliflozin on the renal lesions. Dapagliflozin was administered to SDT fatty rats from 5 to 17 weeks of age. Blood and urinary biochemical parameters were periodically measured. GFR was determined by transdermal GFR monitor at 16 weeks of age and histopathological analysis was performed at 17 weeks of age. SDT fatty rat developed severe hyperglycemia and exhibited pathophysiological abnormalities in the kidney, such as an increased GFR, glomerular hypertrophy and tissue lesions. Dapagliflozin achieved good glycemic control during the experimental period, inhibited the increase in GFR, and improved histopathological abnormalities in tubules. These results suggest that the SDT fatty rat is a useful model for analyzing the pathogenesis of diabetic nephropathy during its early stage and dapagliflozin improves not only hyperglycemia but also glomerular hyperfiltration and tubule lesions in SDT fatty rat.

Glomerular hypertrophy is crucial for podocyte damage and proteinuria. Our previous study showed that fructose induced podocyte injury. However, the molecular mechanism underlying podocyte hypertrophy under fructose is unclear. We observed that fructose significantly initiated the hypertrophy in rat glomeruli and cultured differentiated human podocytes (HPCs). Consistently, it induced inflammatory response with the down-regulation of zinc-finger protein tristetraprolin (TTP) and the activation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling in these animal and cell models. Subsequently, high-expression of miR-92a-3p and its target protein cyclin-dependent kinase inhibitor p57 (P57) down-regulation, representing the abnormal proliferation and apoptosis, were observedin vivoandin vitro. Moreover, fructose increased ketohexokinase-A (KHK-A) in rat glomeruli and HPCs. Animal-free recombinant human IL-6, maslinic acid andTTPsiRNA were used to manifest that fructose may decrease TTP to activate IL-6/STAT3 signaling in podocyte overproliferation and apoptosis, causing podocyte hypertrophy.KHK-AsiRNA transfection further demonstrated that the inactivation of IL-6/STAT3 to relieve podocyte hypertrophy mediated by inhibiting KHK-A to increase TTP may be a novel strategy for fructose-associated podocyte injury and proteinuria.Graphic Abstract

Glomerular hypertrophy is an early morphological alteration in diabetic nephropathy. Cyclin-Dependent Kinases have been shown to be required for high glucose (HG)-induced hypertrophy; however, the upstream regulators of CDKN1B in glomerular hypertrophy remain unclear. Herein we describe a novel pathway in which Long noncoding RNA (lncRNA) NEAT1 regulates the progression of mesangial cell hypertrophy via a competing endogenous RNA (ceRNA) mechanism. Real-time PCR was performed to detect the relative NEAT1 and miR-222-3p expressions and further confirmed the relationship between NEAT1 and miR-222-3p. Cell cycle was evaluated by flow cytometry. The related mechanisms were explored by Western blot, RNA immunoprecipitation and chromatin immunoprecipitation assay. We show that NEAT1 forms double stranded RNA (dsRNA) with miR-222-3p, thus limiting miR-222-3p’s binding with CDKN1B. This release of CDKN1B mRNA leads to elevated CDKN1B protein expression, resulting in hypertrophy. In addition, we demonstrated that STAT3 which is activated by HG induces the transcription of NEAT1 by binding to its promoter. Our findings underscore an unexpected role of lncRNAs on gene regulation and introduce a new mode of proliferation regulation in mesangial cells.

Rationale & Objective The response to corticosteroid therapy may differ among patients with minimal change disease (MCD). Previous studies have suggested that glomerular hypertrophy or low areal glomerular density in biopsy specimens, which may be related to fewer nephrons, is associated with such a difference. We examined the associations between nephron number and the therapeutic response to corticosteroids in patients with MCD. Study Design Retrospective cohort study. Setting & Participants 75 adult patients with a histologic diagnosis of MCD. Exposure Nephron number per kidney estimated based on the combination of unenhanced computed tomography and nonsclerotic volumetric glomerular density in kidney biopsy specimens. Outcomes Complete remission and relapse following corticosteroid therapy. Analytical Approach Multivariable Cox proportional hazard analyses of associations between factors, including nephron number, and outcomes. Results Mean age of patients was 45.9 years and 60.0% were men. Patients had an estimated glomerular filtration rate of 64.6 mL/min/1.73 m2 and proteinuria of 8.7 g/d. The estimated total number of nonsclerotic glomeruli ranged from 1.07 to 18.77 ×105 per kidney among all patients. There were no significant differences in total amounts or selectivity of urinary protein excretion at biopsy among the tertile groups categorized by nephron number. All patients responded to corticosteroid therapy, but those with fewer nephrons had a delayed achievement of complete remission. Multivariable Cox proportional hazard analyses identified nephron number as a significant independent explanatory variable for the achievement of complete remission, with a hazard ratio of 1.10 (95% CI, 1.02-1.19)/100,000 nephrons per kidney. Nephron number in these patients was not associated with achievement of partial remission or relapse following complete remission. Limitation Retrospective design and sampling bias of needle biopsy. Conclusions A small nephron number in patients with MCD is associated with longer time to complete remission., Graphical abstract

Introduction: Extra efferent arterioles, also known as polar vasculosis (PV), are often observed in the glomerular vascular pole and are associated with glomerular hypertrophy, indicating early recurrent diabetic kidney disease (DKD) in renal allografts. However, its significance in patients without diabetes remains uncertain. Methods: A total of 9,004 renal allograft biopsy specimens obtained between January 2007 and December 2017 at Tokyo Women’s Medical University were retrospectively analyzed to examine the clinical and pathological significance of PV in renal allografts. PV was identified in 186 biopsy specimens obtained from 165 patients. The PV group comprised 46 patients; 35 patients without DKD and 11 patients with DKD as the initial cause of ESRD, whose clinical information was available and treated with the calcineurin inhibitor (CNI) tacrolimus. The non-PV group comprising patients with renal allografts matched for age and postoperative day included 93 patients without DKD and 16 patients with DKD as the initial cause of ESRD. Results: In patients with nondiabetic renal allografts, systolic blood pressure was significantly higher in the PV group than in the non-PV group. The trough tacrolimus levels during the overall study period and at 2 weeks, 1 month, and 2 years after transplantation were significantly higher in the PV group compared with the non-PV group. Glomerulomegaly was significantly more common. Moreover, ah and aah scores in Banff score were significantly higher in the PV group than in the non-PV group. In those with diabetic renal allografts, although the clinical parameters and tacrolimus trough levels in all time periods were not significantly different between the PV and non-PV groups, the ah score was significantly higher in the PV group. Conclusion: PV was associated with CNI toxicity in nondiabetic but not in diabetic renal allografts. The pathogenesis of PV in renal allografts is considered to be multifactorial.