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

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.

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Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

Biomedicines ◽

10.3390/biomedicines9050457 ◽

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

AJP Renal Physiology ◽

10.1152/ajprenal.00205.2009 ◽

2009 ◽

Vol 297 (4) ◽

pp. F923-F931 ◽

Cited By ~ 34

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.

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Review of Herbal Traditional Chinese Medicine for the Treatment of Diabetic Nephropathy

Journal of Diabetes Research ◽

10.1155/2016/5749857 ◽

2016 ◽

Vol 2016 ◽

pp. 1-18 ◽

Cited By ~ 28

Author(s):

Guang-dong Sun ◽

Chao-yuan Li ◽

Wen-peng Cui ◽

Qiao-yan Guo ◽

Chang-qing Dong ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Diabetic Patients ◽

Protective Effects ◽

Chronic Complications ◽

Poor Treatment ◽

Stage Renal Disease ◽

End Stage ◽

And Control

Diabetic nephropathy (DN) is the most serious chronic complications of diabetes; 20–40% of diabetic patients develop into end stage renal disease (ESRD). However, exact pathogenesis of DN is not fully clear and we have great difficulties in curing DN; poor treatment of DN led to high chances of mortality worldwide. A lot of western medicines such as ACEI and ARB have been demonstrated to protect renal function of DN but are not enough to delay or retard the progression of DN; therefore, exploring exact and feasible drug is current research hotspot in medicine. Traditional Chinese medicine (TCM) has been widely used to treat and control diabetes and its complications such as DN in a lot of scientific researches, which will give insights into the mechanism of DN, but they are not enough to reveal all the details. In this paper, we summarize the applications of herbal TCM preparations, single herbal TCM, and/or monomers from herbal TCM in the treatment of DN in the recent 10 years, depicting the renal protective effects and the corresponding mechanism, through which we shed light on the renal protective roles of TCM in DN with a particular focus on the molecular basis of the effect and provide a beneficial supplement to the drug therapy for DN.

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Interleukin-22 mediated renal metabolic reprogramming via PFKFB3 to treat kidney injury

10.1101/2020.08.04.237347 ◽

2020 ◽

Author(s):

Wei Chen ◽

Yilan Shen ◽

Jiajun Fan ◽

Xian Zeng ◽

Xuyao Zhang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Kidney Diseases ◽

Kidney Injury ◽

Kidney Damage ◽

Metabolic Reprogramming ◽

Protective Effects ◽

Interleukin 22 ◽

Renal Tubular ◽

Stage Renal Disease ◽

End Stage

AbstractKidney damage initiates the deteriorating metabolic states in tubule cells that lead to the development of end-stage renal disease (ESTD). Interleukin 22 (IL-22) is an effective therapeutic antidote for kidney injury via promoting kidney recovery, but little is known about the underlying molecular mechanisms. Here we first provide evidence that IL-22 attenuates kidney injury via metabolic reprogramming of renal tubular epithelial cells (TECs). Specifically, our data suggest that IL-22 regulates mitochondrial function and glycolysis in damaged TECs. Further observations indicate that IL-22 alleviates the accumulation of mitochondrial reactive oxygen species (ROS) and dysfunctional mitochondria via the induction of AMPK/AKT signaling and PFBFK3 activities. In mice, amelioration of kidney injury and necrosis and improvement of kidney functions via regulation of these metabolism relevant signaling and mitochondrial fitness of recombinant IL-22 are certificated in cisplatin induced kidney damage and diabetic nephropathy (DN) animal models. Taken together, our findings unravel new mechanistic insights into protective effects of IL-22 on kidney and highlight the therapeutic opportunities of IL-22 and the involved metabolic regulators in various kidney diseases.

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eEOC-mediated modulation of endothelial autophagy, senescence, and EnMT in murine diabetic nephropathy

AJP Renal Physiology ◽

10.1152/ajprenal.00650.2013 ◽

2014 ◽

Vol 307 (6) ◽

pp. F686-F694 ◽

Cited By ~ 16

Author(s):

D. Patschan ◽

K. Schwarze ◽

E. Henze ◽

J. U. Becker ◽

S. Patschan ◽

...

Keyword(s):

Endothelial Cells ◽

Diabetic Nephropathy ◽

Interstitial Fibrosis ◽

Kidney Injury ◽

Microvascular Damage ◽

Mesenchymal Transition ◽

Morphogenetic Protein ◽

Endothelial To Mesenchymal Transition ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy is the most frequent single cause of end-stage renal disease in our society. Microvascular damage is a key event in diabetes-associated organ malfunction. Early endothelial outgrowth cells (eEOCs) act protective in murine acute kidney injury. The aim of the present study was to analyze consequences of eEOC treatment of murine diabetic nephropathy with special attention on endothelial-to-mesenchymal transdifferentiation, autophagy, senescence, and apoptosis. Male C57/Bl6N mice (8–12 wk old) were treated with streptozotocin for 5 consecutive days. Animals were injected with untreated or bone morphogenetic protein (BMP)-5-pretreated syngeneic murine eEOCs on days 2 and 5 after the last streptozotocin administration. Four, eight, and twelve weeks later, animals were analyzed for renal function, proteinuria, interstitial fibrosis, endothelial-to-mesenchymal transition, endothelial autophagy, and senescence. In addition, cultured mature murine endothelial cells were investigated for autophagy, senescence, and apoptosis in the presence of glycated collagen. Diabetes-associated renal dysfunction (4 and 8 wk) and proteinuria (8 wk) were partly preserved by systemic cell treatment. At 8 wk, antiproteinuric effects were even more pronounced after the injection of BMP-5-pretreated cells. The latter also decreased mesenchymal transdifferentiation of the endothelium. At 8 wk, intrarenal endothelial autophagy (BMP-5-treated cells) and senescence (native and BMP-5-treated cells) were reduced. Autophagy and senescence in/of cultured mature endothelial cells were dramatically reduced by eEOC supernatant (native and BMP-5). Endothelial apoptosis decreased after incubation with eEOC medium (native and BMP-5). eEOCs act protective in diabetic nephropathy, and such effects are significantly stimulated by BMP-5. The cells modulate endothelial senescence, autophagy, and apoptosis in a protective manner. Thus, the renal endothelium could serve as a therapeutic target in diabetes-associated kidney dysfunction.

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The Role of MicroRNAs in Diabetic Nephropathy

Journal of Diabetes Research ◽

10.1155/2014/920134 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 39

Author(s):

Hao Wu ◽

Lili Kong ◽

Shanshan Zhou ◽

Wenpeng Cui ◽

Feng Xu ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Critical Role ◽

Good Prospect ◽

Protective Effects ◽

Protein Coding ◽

Diagnostic Strategies ◽

Pathogenic Factors ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy (DN), as one of the chronic complications of diabetes, is the major cause of end-stage renal disease. However, the pathogenesis of this disease is not fully understood. In recent years, research on microRNAs (miRNAs) has become a hotspot because of their critical role in regulating posttranscriptional levels of protein-coding genes that may serve as key pathogenic factors in diseases. Several miRNAs were found to participate in the pathogenesis of DN, while others showed renal protective effects. Therefore, targeting miRNAs that are involved in DN may have a good prospect in the treatment of the disease. The aim of this review is to summarize DN-related miRNAs and provide potential targets for diagnostic strategies and therapeutic intervention.

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Blockade of the Adenosine A3 Receptor Attenuates Caspase 1 Activation in Renal Tubule Epithelial Cells and Decreases Interleukins IL-1β and IL-18 in Diabetic Rats

International Journal of Molecular Sciences ◽

10.3390/ijms20184531 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4531 ◽

Cited By ~ 2

Author(s):

Wallys Garrido ◽

Claudia Jara ◽

Angelo Torres ◽

Raibel Suarez ◽

Claudio Cappelli ◽

...

Keyword(s):

Kidney Injury ◽

Diabetic Rats ◽

Selective Blockade ◽

Caspase 1 ◽

Renal Tubular Epithelium ◽

Renal Tubular ◽

Stage Renal Disease ◽

End Stage ◽

Hk2 Cells

Diabetic nephropathy (DN) is the main cause of end-stage renal disease, which remains incurable. The progression of DN is associated with progressive and irreversible renal fibrosis and also high levels of adenosine. Our aim was to evaluate the effects of ADORA3 antagonism on renal injury in streptozotocin-induced diabetic rats. An ADORA3 antagonist that was administered in diabetic rats greatly inhibited the levels of inflammatory interleukins IL-1β and IL-18, meanwhile when adenosine deaminase was administered, there was a non-selective attenuation of the inflammatory mediators IL-1β, IL-18, IL-6, and induction of IL-10. The ADORA3 antagonist attenuated the high glucose-induced activation of caspase 1 in HK2 cells in vitro. Additionally, ADORA3 antagonisms blocked the increase in caspase 1 and the nuclear localization of NFκB in the renal tubular epithelium of diabetic rats, both events that are involved in regulating the production and activation of IL-1β and IL-18. The effects of the A3 receptor antagonist resulted in the attenuation of kidney injury, as evidenced by decreased levels of the pro-fibrotic marker α-SMA at histological levels and the restoration of proteinuria in diabetic rats. We conclude that ADORA3 antagonism represents a potential therapeutic target that mechanistically works through the selective blockade of the NLRP3 inflammasome.

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Potential Renoprotective Agents through Inhibiting CTGF/CCN2 in Diabetic Nephropathy

Journal of Diabetes Research ◽

10.1155/2015/962383 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 10

Author(s):

Songyan Wang ◽

Bing Li ◽

Chunguang Li ◽

Wenpeng Cui ◽

Lining Miao

Keyword(s):

Diabetic Nephropathy ◽

Therapeutic Agents ◽

Tissue Growth ◽

Protective Effects ◽

Potential Therapeutic Target ◽

Multiple Factors ◽

The One ◽

Stage Renal Disease ◽

End Stage ◽

Ccn2 Expression

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The development and progression of DN might involve multiple factors. Connective tissue growth factor (CCN2, originally known as CTGF) is the one which plays a pivotal role. Therefore, increasing attention is being paid to CCN2 as a potential therapeutic target for DN. Up to date, there are also many drugs or agents which have been shown for their protective effects against DN via different mechanisms. In this review, we only focus on the potential renoprotective therapeutic agents which can specifically abolish CCN2 expression or nonspecifically inhibit CCN2 expression for retarding the development and progression of DN.

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Carvedilol Ameliorates Early Diabetic Nephropathy in Streptozotocin-Induced Diabetic Rats

BioMed Research International ◽

10.1155/2014/105214 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 10

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.

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SIRT1: Mechanism and Protective in Diabetic Nephropathy

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666201029143606 ◽

2020 ◽

Vol 20 ◽

Author(s):

Jing Ji ◽

Pengyu Tao ◽

Qian Wang ◽

Lingxing Li ◽

Yuzhen Xu

Keyword(s):

Diabetic Nephropathy ◽

Cellular Response ◽

Symptomatic Relief ◽

Kidney Injury ◽

Protective Mechanism ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Renal Tubular ◽

Stage Renal Disease ◽

End Stage

: Diabetic nephropathy (DN) is referred to as the microvascular complication of the kidneys induced by insufficient production of insulin or an ineffective cellular response to insulin, and is the main cause of end-stage renal disease. Currently, available therapies provide only symptomatic relief and fail to improve the outcome of diabetic nephropathy. Studies on diabetic animals had shown overexpression of SIRT1 in both podocytes and renal tubular cells attenuated proteinuria and kidney injury in animal model of DN. Sirt1 exerts renoprotective effects in DKD in part through the deacetylation of transcription factors involved in the disease pathogenesis, such as NF-кB, Smad3, FOXO and p53. The purpose of this review is to highlight the protective mechanism of SIRT1 involved in the pathogenesis of diabetic nephropathy.

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