scholarly journals Carvedilol Ameliorates Early Diabetic Nephropathy in Streptozotocin-Induced Diabetic Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Mohamed A. Morsy ◽  
Salwa A. Ibrahim ◽  
Entesar F. Amin ◽  
Maha Y. Kamel ◽  
Soha A. Abdelwahab ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Protective Effect ◽  
Histopathological Examination ◽  
Electron Microscopic Examination ◽  
Diabetic Rats ◽  
Electron Microscopic ◽  
Podocyte Injury ◽  
Stage Renal Disease ◽  
End Stage ◽  
Early Diabetic Nephropathy

Diabetic nephropathy results in end-stage renal disease. On the other hand, carvedilol has been reported to have various pharmacological properties. The aim of this study therefore is to evaluate the possible protective effect of carvedilol on streptozotocin-induced early diabetic nephropathy and various mechanisms underlie this effect in rats. Single i.p. injection of streptozotocin (65 mg/kg) was administered to induce early diabetic nephropathy in Wistar rats. Oral administration of carvedilol at a dose level of 1 and 10 mg/kg daily for 4 weeks resulted in nephroprotective effect as evident by significant decrease in serum creatinine level, urinary albumin/creatinine ratio, and kidney index as well as renal levels of malondialdehyde, nitric oxide, tumor necrosis factor-α, and cyclooxygenase-2 with a concurrent increase in creatinine clearance and renal reduced glutathione level compared to diabetic untreated rats. The protective effect of carvedilol was confirmed by renal histopathological examination. The electron microscopic examination indicated that carvedilol could effectively ameliorate glomerular basement membrane thickening and podocyte injury. In conclusion, carvedilol protects rats against streptozotocin-induced early diabetic nephropathy possibly, in part, through its antioxidant as well as anti-inflammatory activities, and ameliorating podocyte injury.

Postischemic inflammatory syndrome: a critical mechanism of progression in diabetic nephropathy

2009 ◽  
Vol 297 (4) ◽  
pp. F923-F931 ◽  
Author(s):  
K. J. Kelly ◽  
James L. Burford ◽  
Jesus H. Dominguez
Keyword(s):  
Diabetic Nephropathy ◽  
Flow Velocity ◽  
Diabetic Rats ◽  
Renal Ischemia ◽  
Sham Surgery ◽  
Acute Renal Ischemia ◽  
Stage Renal Disease ◽  
End Stage ◽  
Inflammatory Syndrome ◽  
Obese Diabetic Rats

Diabetes is a major epidemic, and diabetic nephropathy is the most common cause of end-stage renal disease. Two critical components of diabetic nephropathy are persistent inflammation and chronic renal ischemia from widespread vasculopathy. Moreover, acute ischemic renal injury is common in diabetes, potentially causing chronic kidney disease or end-stage renal disease. Accordingly, we tested the hypothesis that acute renal ischemia accelerates nephropathy in diabetes by activating proinflammatory pathways. Lean and obese-diabetic ZS rats (F1 hybrids of spontaneously hypertensive heart failure and Zucker fatty diabetic rats) were subjected to bilateral renal ischemia or sham surgery before the onset of proteinuria. The postischemic state in rats with obesity-diabetes was characterized by progressive chronic renal failure, increased proteinuria, and renal expression of proinflammatory mediators. Leukocyte number in obese-diabetic rat kidney was markedly increased for months after ischemia. Intrarenal blood flow velocity was decreased after ischemia in lean control and obese-diabetic rats, although it recovered in lean rats. At 2 mo after ischemia, blood flow velocity decreased further in sham-surgery and postischemia obese-diabetic rats, so that RBC flow velocity was only 39% of control in the obese-diabetic rats after ischemia. In addition, microvascular density remained depressed at 2 mo in kidneys of obese-diabetic rats after ischemia. Abnormal microvascular permeability and increases in interstitial fibrosis and apoptotic renal cell death were also more pronounced after ischemia in obese-diabetic rats. These data support the hypothesis that acute renal ischemia in obesity-diabetes severely aggravates chronic inflammation and vasculopathy, creating a self-perpetuating postischemia inflammatory syndrome, which accelerates renal failure.

scholarly journals Research Progress on the Pathological Mechanisms of Podocytes in Diabetic Nephropathy

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Lili Zhang ◽  
Zhige Wen ◽  
Lin Han ◽  
Yujiao Zheng ◽  
Yu Wei ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Morphological Changes ◽  
Research Progress ◽  
Podocyte Injury ◽  
Functional Changes ◽  
Pathological Mechanism ◽  
Podocyte Detachment ◽  
Stage Renal Disease ◽  
End Stage ◽  
Multiple Signaling

Diabetic nephropathy (DN) is not only an important microvascular complication of diabetes but also the main cause of end-stage renal disease. Studies have shown that the occurrence and development of DN are closely related to morphological and functional changes in podocytes. A series of morphological changes after podocyte injury in DN mainly include podocyte hypertrophy, podocyte epithelial-mesenchymal transdifferentiation, podocyte detachment, and podocyte apoptosis; functional changes mainly involve podocyte autophagy. More and more studies have shown that multiple signaling pathways play important roles in the progression of podocyte injury in DN. Here, we review research progress on the pathological mechanism of morphological and functional changes in podocytes associated with DN, to provide a new target for delaying the occurrence and development of this disorder.

scholarly journals ATF4 promotes renal tubulointerstitial fibrosis by suppressing autophagy in diabetic nephropathy

2020 ◽  
Author(s):  
Qiuer Liang ◽  
Tianhao Liu ◽  
Tingting Guo ◽  
Wencong Tao ◽  
Xudong Chen ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Western Blot ◽  
High Glucose ◽  
Microscopic Analysis ◽  
Tubulointerstitial Fibrosis ◽  
Autophagic Flux ◽  
Electron Microscopic ◽  
Renal Tubulointerstitial Fibrosis ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background Diabetic nephropathy (DN) is the dominant cause of end-stage renal disease which is characterized by extracellular matrix accumulation. The purpose of this study was to investigate the role of activating transcription factor 4 (ATF4) in regulating renal fibrosis and autophagy in DN. Methods Streptozotocin (STZ) was administered to heterozygous ATF4 knockout (KO) and wild-type (WT) mice via an intraperitoneal injection to induce DN. NRK-52E cells were cultured in high glucose to mimic diabetic pathological. qRT-PCR, western blot, immunofluorescence, histology and electron microscopic analysis were performed. The autophagy flow was observed by tandem mRFP-GFP-LC3 fluorescence microscopy. Results DN mice experienced severe renal injury and fibrosis and showed increased expression of ATF4 and inhibition of autophagy in kidney tissues. STZ-induced ATF4 KO mice showed significant improvement in urinary albumin, serum creatinine and blood urea nitrogen and the pathological changes of renal tubulointerstitial fibrosis compared with STZ-induced WT mice. Furthermore, western blot assays and immunofluorescence staining revealed that inhibition of ATF4 could restore autophagy in DN mice. Overexpression of ATF4 in NRK-52E cells cultured in high glucose condition suppressed autophagy and upregulated Col-IV expression, while inhibition of ATF4 could increase the number of the autophagosomes, improve autophagic flux and decrease Col-IV level. Conclusion Our study provided the first evidence of a crucial role for ATF4 in inhibiting autophagy against diabetic kidney damage. Suppression of ATF4 may be an effective therapy in restraining renal tubulointerstitial fibrosis in DN.

scholarly journals Protective Effects of Purple Rice Husk against Diabetic Nephropathy by Modulating PGC-1α/SIRT3/SOD2 Signaling and Maintaining Mitochondrial Redox Equilibrium in Rats

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1224
Author(s):  
Orawan Wongmekiat ◽  
Narissara Lailerd ◽  
Anongporn Kobroob ◽  
Wachirasek Peerapanyasut
Keyword(s):  
Diabetic Nephropathy ◽  
Rice Husk ◽  
Agricultural Waste ◽  
Kidney Injury ◽  
Diabetic Rats ◽  
Milling Process ◽  
Protective Effects ◽  
Redox Equilibrium ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is the primary cause of end-stage renal disease worldwide. Oxidative stress and mitochondrial dysfunction are central to its pathogenesis. Rice husk, the leftover from the milling process, is a good source of phytochemicals with antioxidant activity. This study evaluated the possible protection of purple rice husk extract (PRHE) against diabetic kidney injury. Type 2 diabetic rats were given vehicle, PRHE, metformin, and PRHE+metformin, respectively, while nondiabetic rats received vehicle. After 12 weeks, diabetic rats developed nephropathy as proven by metabolic alterations (increased blood glucose, insulin, HOMA-IR, triglycerides, cholesterol) and renal abnormalities (podocyte injury, microalbuminuria, increased serum creatinine, decreased creatinine clearance). Treatment with PRHE, metformin, or combination diminished these changes, improved mitochondrial function (decreased mitochondrial swelling, reactive oxygen species production, membrane potential changes), and reduced renal oxidative damage (decreased lipid peroxidation and increased antioxidants). Increased expression of PGC-1α, SIRT3, and SOD2 and decreased expression of Ac-SOD2 correlated with the beneficial outcomes. HPLC revealed protocatechuic acid and cyanidin-3-glucoside as the key components of PRHE. The findings indicate that PRHE effectively protects against the development of DN by retaining mitochondrial redox equilibrium via the regulation of PGC-1α-SIRT3-SOD2 signaling. This study creates an opportunity to develop this agricultural waste into a useful health product for diabetes.

scholarly journals Silencing of miR-150-5p Ameliorates Diabetic Nephropathy by Targeting SIRT1/p53/AMPK Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenmin Dong ◽  
Huiqian Zhang ◽  
Cheng Zhao ◽  
Yun Luo ◽  
Ying Chen
Keyword(s):  
Diabetic Nephropathy ◽  
Kidney Tissue ◽  
Protective Role ◽  
Sirtuin 1 ◽  
Podocyte Injury ◽  
Stage Renal Disease ◽  
End Stage ◽  
Amp Activated Protein Kinase

Diabetic nephropathy (DN) is a common complication of diabetes and an important cause of end-stage renal disease. Increasing evidence suggests that microRNAs (miRNAs) regulate the development of DN. In a preliminary study, high levels of miR-150-5p were detected in the serum and urine of patients with DN. Consequently, we investigated the effect and mechanism of action of miR-150-5p in DN in vitro and in vivo. Our results showed that inhibition of miR-150-5p reversed high glucose-induced podocyte injury and Streptozocin (STZ)-induced diabetic nephropathy in mice. Further analysis revealed that miR-150-5p targeted the 3′ untranslated region (UTR) of sirtuin 1 (SIRT1), consequently decreasing SIRT1 levels in podocytes. Importantly, we found that the silencing of miR-150-5p promoted the interaction between SIRT1 and p53, causing the suppression of p53 acetylation in podocytes and kidney tissue. This resulted in the stimulation of AMP-activated protein kinase (AMPK)-dependent autophagy. In conclusion, our study demonstrated that the silencing of miR-150-5p played a reno-protective role in DN mice through targeting SIRT1.

scholarly journals Targeted Proteomics of Isolated Glomeruli from the Kidneys of Diabetic Rats: Sorbin and SH3 Domain Containing 2 Is a Novel Protein Associated with Diabetic Nephropathy

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Shinya Nakatani ◽  
Anna Kakehashi ◽  
Eiji Ishimura ◽  
Shotaro Yamano ◽  
Katsuhito Mori ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Actin Polymerization ◽  
Sh3 Domain ◽  
Diabetic Rats ◽  
Stress Fibers ◽  
Isolated Glomeruli ◽  
Oletf Rats ◽  
Associated Proteins ◽  
Stage Renal Disease ◽  
End Stage

To evaluate proteins associated with the development of diabetic nephropathy, a major cause of the end-stage renal disease, we analyzed protein expression in isolated glomeruli from spontaneous type 2 diabetic (OLETF) rats and their age-matched control littermates (LETO) in the early and proteinuric stages of diabetic nephropathy using QSTAR Elite LC-MS/MS. Among the 191 and 218 proteins that were altered significantly in the OLETF rats, twenty-four were actin cytoskeleton-associated proteins implicated in the formation of stress fibers, and the impairment of actin polymerization, intermediate filaments and microtubules. Importantly, sorbin and SH3 domain containing 2 (SORBS2), which is involved in the formation of stress fibers, was significantly upregulated in both stages of diabetic nephropathy (1.49- and 1.97-fold, resp.). Immunohistochemical and quantitative-PCR analyses revealed upregulation of SORBS2 in podocytes of glomeruli of OLETF rats. Our findings suggested that SORBS2 may be associated with the development of diabetic nephropathy possibility by reorganization of actin filaments.

L-carnosine and its Derivatives as New Therapeutic Agents for the Prevention and Treatment of Vascular Complications of Diabetes

2020 ◽  
Vol 27 (11) ◽  
pp. 1744-1763 ◽  
Author(s):  
Stefano Menini ◽  
Carla Iacobini ◽  
Claudia Blasetti Fantauzzi ◽  
Giuseppe Pugliese
Keyword(s):  
Diabetic Nephropathy ◽  
Life Quality ◽  
Vascular Complications ◽  
Carbonyl Stress ◽  
Complications Of Diabetes ◽  
Diabetic Vascular Complications ◽  
Reactive Carbonyl Species ◽  
Stage Renal Disease ◽  
Stress Dependent ◽  
End Stage

Vascular complications are among the most serious manifestations of diabetes. Atherosclerosis is the main cause of reduced life quality and expectancy in diabetics, whereas diabetic nephropathy and retinopathy are the most common causes of end-stage renal disease and blindness. An effective therapeutic approach to prevent vascular complications should counteract the mechanisms of injury. Among them, the toxic effects of Advanced Glycation (AGEs) and Lipoxidation (ALEs) end-products are well-recognized contributors to these sequelae. L-carnosine (β-alanyl-Lhistidine) acts as a quencher of the AGE/ALE precursors Reactive Carbonyl Species (RCS), which are highly reactive aldehydes derived from oxidative and non-oxidative modifications of sugars and lipids. Consistently, L-carnosine was found to be effective in several disease models in which glyco/lipoxidation plays a central pathogenic role. Unfortunately, in humans, L-carnosine is rapidly inactivated by serum carnosinase. Therefore, the search for carnosinase-resistant derivatives of Lcarnosine represents a suitable strategy against carbonyl stress-dependent disorders, particularly diabetic vascular complications. In this review, we present and discuss available data on the efficacy of L-carnosine and its derivatives in preventing vascular complications in rodent models of diabetes and metabolic syndrome. We also discuss genetic findings providing evidence for the involvement of the carnosinase/L-carnosine system in the risk of developing diabetic nephropathy and for preferring the use of carnosinase-resistant compounds in human disease. The availability of therapeutic strategies capable to prevent both long-term glucose toxicity, resulting from insufficient glucoselowering therapy, and lipotoxicity may help reduce the clinical and economic burden of vascular complications of diabetes and related metabolic disorders.

scholarly journals Herba Artemisiae Capillaris Extract Prevents the Development of Streptozotocin-Induced Diabetic Nephropathy of Rat

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Jianan Geng ◽  
Xiaoyan Yu ◽  
Chunyu Liu ◽  
Chengbo Sun ◽  
Menghuan Guo ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Tissue Transglutaminase ◽  
Blood Lipid ◽  
High Dose ◽  
Oxygen Species ◽  
Promising Candidate ◽  
Ecm Degradation ◽  
Stage Renal Disease ◽  
End Stage ◽  
Excessive Accumulation

Diabetic nephropathy (DN) is a major cause of end-stage renal disease throughout the world; until now there is no specific drug available. In this work, we use herba artemisiae capillaris extract (HACE) to alleviate renal fibrosis characterized by the excessive accumulation of extracellular matrix (ECM) in rats, aiming to investigate the protective effect of the HACE on DN. We found that the intragastric treatment of high-dose HACE could reverse the effect of streptozotocin not only to decrease the level of blood glucose and blood lipid in different degree but also further to improve renal functions. It is worth mentioning that the effect of HACE treatment was comparable to the positive drug benazepril. Moreover, we found that HACE treatment could on one hand inhibit oxidative stress in DN rats through regulating enzymatic activity for scavenging reactive oxygen species and on the other hand increase the ECM degradation through regulating the activity of metalloproteinase-2 (MMP-2) and the expression of tissue transglutaminase (tTG), which explained why HACE treatment inhibited ECM accumulation. On the basis of above experimental results, we conclude that HACE prevents DN development in a streptozotocin-induced DN rat model, and HACE is a promising candidate to cure DN in clinic.

scholarly journals Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 457
Author(s):  
Kyeong-Seok Kim ◽  
Jin-Sol Lee ◽  
Jae-Hyeon Park ◽  
Eun-Young Lee ◽  
Jong-Seok Moon ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Early Stage ◽  
Kidney Injury ◽  
Diabetic Patients ◽  
High Morbidity ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Zucker Diabetic Fatty Rats ◽  
Kidney Injury Molecule 1 ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus. After development of DN, patients will progress to end-stage renal disease, which is associated with high morbidity and mortality. Here, we developed early-stage diagnostic biomarkers to detect DN as a strategy for DN intervention. For the DN model, Zucker diabetic fatty rats were used for DN phenotyping. The results revealed that DN rats showed significantly increased blood glucose, blood urea nitrogen (BUN), and serum creatinine levels, accompanied by severe kidney injury, fibrosis and microstructural changes. In addition, DN rats showed significantly increased urinary excretion of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Transcriptome analysis revealed that new DN biomarkers, such as complementary component 4b (C4b), complementary factor D (CFD), C-X-C motif chemokine receptor 6 (CXCR6), and leukemia inhibitory factor (LIF) were identified. Furthermore, they were found in the urine of patients with DN. Since these biomarkers were detected in the urine and kidney of DN rats and urine of diabetic patients, the selected markers could be used as early diagnosis biomarkers for chronic diabetic nephropathy.

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