scholarly journals Geniposide Improves Diabetic Nephropathy by Enhancing ULK1-Mediated Autophagy and Reducing Oxidative Stress through AMPK Activation

2021 ◽  
Vol 22 (4) ◽  
pp. 1651
Author(s):  
Theodomir Dusabimana ◽  
Eun Jung Park ◽  
Jihyun Je ◽  
Kyuho Jeong ◽  
Seung Pil Yun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Interstitial Fibrosis ◽  
Pathological Feature ◽  
Protective Effects ◽  
Pharmacological Agents ◽  
Patients With Diabetes ◽  
Underlying Mechanisms ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is a common pathological feature in patients with diabetes and the leading cause of end-stage renal disease. Although several pharmacological agents have been developed, the management of DN remains challenging. Geniposide, a natural compound has been reported for anti-inflammatory and anti-diabetic effects; however, its role in DN remains poorly understood. This study investigated the protective effects of geniposide on DN and its underlying mechanisms. We used a C57BL/6 mouse model of DN in combination with a high-fat diet and streptozotocin after unilateral nephrectomy and treated with geniposide by oral gavage for 5 weeks. Geniposide effectively improves DN-induced renal structural and functional abnormalities by reducing albuminuria, podocyte loss, glomerular and tubular injury, renal inflammation and interstitial fibrosis. These changes induced by geniposide were associated with an increase of AMPK activity to enhance ULK1-mediated autophagy response and a decrease of AKT activity to block oxidative stress, inflammation and fibrosis in diabetic kidney. In addition, geniposide increased the activities of PKA and GSK3β, possibly modulating AMPK and AKT pathways, efficiently improving renal dysfunction and ameliorating the progression of DN. Conclusively, geniposide enhances ULK1-mediated autophagy and reduces oxidative stress, inflammation and fibrosis, suggesting geniposide as a promising treatment for DN.

scholarly journals Apoptosis-Associated Speck-Like Protein Containing a CARD Deletion Ameliorates Unilateral Ureteral Obstruction Induced Renal Fibrosis and Endoplasmic Reticulum Stress in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yao Xu ◽  
Yuqing Liu ◽  
Honglei Guo ◽  
Wei Ding
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Pathological Feature ◽  
Ureter Obstruction ◽  
Underlying Mechanisms ◽  
Stage Renal Disease ◽  
End Stage

Inflammation might be one of the essential underlying mechanisms of renal fibrosis, which is considered a key pathological feature of end-stage renal disease and is closely associated with proteinuria and decreased renal function. Apoptosis-associated speck-like protein containing a CARD (ASC), identified as the central structure of inflammasome, is involved in the progression of interstitial fibrosis; however, its signal transduction pathways remain unclear. In the present study, we performed unilateral ureter obstruction (UUO) in both wild-type and ASC deletion mice to determine the contribution of ASC to renal fibrosis. Compared with control groups, UUO significantly induced renal fibrosis and collagen deposition, as evidenced by photomicrographs. ASC deletion attenuated renal injury, reduced cell infiltration and the release of inflammatory cytokines, protected against apoptosis, and downregulated the PRKR-like endoplasmic reticulum kinase (PERK) pathway of endoplasmic reticulum (ER) stress. Our data identify a novel role of ASC in the regulation of renal fibrosis and ER stress after UUO, strongly indicating that ASC could serve as an attractive target in the treatment of chronic kidney disease.

scholarly journals The Role of Non-coding RNAs in Diabetic Nephropathy-Related Oxidative Stress

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoyun He ◽  
Gaoyan Kuang ◽  
Yi Zuo ◽  
Shuangxi Li ◽  
Suxian Zhou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Interstitial Fibrosis ◽  
Rna Molecules ◽  
Non Coding Rnas ◽  
Molecular Therapeutic ◽  
Stage Renal Disease ◽  
End Stage ◽  
Molecular Therapeutic Targets

Diabetic nephropathy (DN) is one of the main complications of diabetes and the main cause of diabetic end-stage renal disease, which is often fatal. DN is usually characterized by progressive renal interstitial fibrosis, which is closely related to the excessive accumulation of extracellular matrix and oxidative stress. Non-coding RNAs (ncRNAs) are RNA molecules expressed in eukaryotic cells that are not translated into proteins. They are widely involved in the regulation of biological processes, such as, chromatin remodeling, transcription, post-transcriptional modification, and signal transduction. Recent studies have shown that ncRNAs play an important role in the occurrence and development of DN and participate in the regulation of oxidative stress in DN. This review clarifies the functions and mechanisms of ncRNAs in DN-related oxidative stress, providing valuable insights into the prevention, early diagnosis, and molecular therapeutic targets of DN.

Could Antioxidant Supplementation Delay Progression of Cardiovascular Disease in End-Stage Renal Disease Patients?

2020 ◽  
Vol 19 (1) ◽  
pp. 41-54 ◽  
Author(s):  
Stefanos Roumeliotis ◽  
Athanasios Roumeliotis ◽  
Xenia Gorny ◽  
Peter R. Mertens
Keyword(s):  
Oxidative Stress ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Close Association ◽  
Omega 3 ◽  
Endstage Renal Disease ◽  
Increased Risk ◽  
Underlying Mechanisms ◽  
Stage Renal Disease ◽  
End Stage

In end-stage renal disease patients, the leading causes of mortality are of cardiovascular (CV) origin. The underlying mechanisms are complex, given that sudden heart failure is more common than acute myocardial infarction. A contributing role of oxidative stress is postulated, which is increased even at early stages of chronic kidney disease, is gradually augmented in parallel to progression to endstage renal disease and is further accelerated by renal replacement therapy. Oxidative stress ensues when there is an imbalance between reactive pro-oxidants and physiologically occurring electron donating antioxidant defence systems. During the last decade, a close association of oxidative stress with accelerated atherosclerosis and increased risk for CV and all-cause mortality has been established. Lipid peroxidation has been identified as a trigger for endothelial dysfunction, the first step towards atherogenesis. In order to counteract the deleterious effects of free radicals and thereby ameliorate, or delay, CV disease, exogenous administration of antioxidants has been proposed. Here, we attempt to summarize existing data from studies that test antioxidants for CV protection, such as vitamins E and C, statins, omega-3 fatty acids and N-acetylcysteine.

scholarly journals Serum Prolidase Activity and Oxidative Stress in Diabetic Nephropathy and End Stage Renal Disease: A Correlative Study with Glucose and Creatinine

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Akhilesh Kumar Verma ◽  
Subhash Chandra ◽  
Rana Gopal Singh ◽  
Tej Bali Singh ◽  
Shalabh Srivastava ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Blood Glucose ◽  
Renal Disease ◽  
Serum Creatinine ◽  
End Stage Renal Disease ◽  
Prolidase Activity ◽  
Stage Renal Disease ◽  
End Stage ◽  
And Oxidative Stress

Association of oxidative stress and serum prolidase activity (SPA) has been reported in many chronic diseases. The study was aimed at evaluating the correlation of glucose and creatinine to SPA and oxidative stress in patients with diabetic nephropathy (DN) and end stage renal disease (ESRD) concerned with T2DM. 50 healthy volunteers, 50 patients with T2DM, 86 patients with DN, and 43 patients with ESRD were considered as control-1, control-2, case-1, and case-2, respectively. Blood glucose, creatinine, SPA, total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) were measured by colorimetric tests. SPA, TOS, and OSI were significantly increased in case-1 and case-2 than control-1 and control-2, while TAS was significantly decreased(P<0.001). Blood glucose was linearly correlated to SPA, TOS, TAS, and OSI in control-2, case-1 and case-2(P<0.001). Serum creatinine was linearly correlated with SPA, TOS, TAS and OSI in control-2 and case-1(P<0.001). In case-2, serum creatinine was significantly correlated with SPA only(P<0.001). Thus, the study concluded that SPA and oxidative stress significantly correlated with blood glucose and creatinine. SPA, TOS, TAS, and OSI can be used as biomarkers for diagnosis of kidney damage.

scholarly journals Epigenetic Alterations in Podocytes in Diabetic Nephropathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Erina Sugita ◽  
Kaori Hayashi ◽  
Akihito Hishikawa ◽  
Hiroshi Itoh
Keyword(s):  
Dna Damage ◽  
Diabetic Nephropathy ◽  
Epigenetic Changes ◽  
Epigenetic Alterations ◽  
Human Samples ◽  
Differentiated Cells ◽  
Damage Repair ◽  
Patients With Diabetes ◽  
Stage Renal Disease ◽  
End Stage

Recently, epigenetic alterations have been shown to be involved in the pathogenesis of diabetes and its complications. Kidney podocytes, which are glomerular epithelial cells, are important cells that form a slit membrane—a barrier for proteinuria. Podocytes are terminally differentiated cells without cell division or replenishment abilities. Therefore, podocyte damage is suggested to be one of the key factors determining renal prognosis. Recent studies, including ours, suggest that epigenetic changes in podocytes are associated with chronic kidney disease, including diabetic nephropathy. Furthermore, the association between DNA damage repair and epigenetic changes in diabetic podocytes has been demonstrated. Detection of podocyte DNA damage and epigenetic changes using human samples, such as kidney biopsy and urine-derived cells, may be a promising strategy for estimating kidney damage and renal prognoses in patients with diabetes. Targeting epigenetic podocyte changes and associated DNA damage may become a novel therapeutic strategy for preventing progression to end-stage renal disease (ESRD) and provide a possible prognostic marker in diabetic nephropathy. This review summarizes recent advances regarding epigenetic changes, especially DNA methylation, in podocytes in diabetic nephropathy and addresses detection of these alterations in human samples. Additionally, we focused on DNA damage, which is increased under high-glucose conditions and associated with the generation of epigenetic changes in podocytes. Furthermore, epigenetic memory in diabetes is discussed. Understanding the role of epigenetic changes in podocytes in diabetic nephropathy may be of great importance considering the increasing diabetic nephropathy patient population in an aging society.

scholarly journals Enhancing kidney DDAH-1 expression by adenovirus delivery reduces ADMA and ameliorates diabetic nephropathy

2020 ◽  
Vol 318 (2) ◽  
pp. F509-F517 ◽  
Author(s):  
Michael D. Wetzel ◽  
Ting Gao ◽  
Kristen Stanley ◽  
Timothy K. Cooper ◽  
Sidney M. Morris ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Diabetic Nephropathy ◽  
Fluorescent Protein ◽  
Thiobarbituric Acid ◽  
Renal Tissue ◽  
Diabetic Mice ◽  
Patients With Diabetes ◽  
Green Fluorescent ◽  
Stage Renal Disease

Endothelial dysfunction, characterized by reduced bioavailability of nitric oxide and increased oxidative stress, is a hallmark characteristic in diabetes and diabetic nephropathy (DN). High levels of asymmetric dimethylarginine (ADMA) are observed in several diseases including DN and are a strong prognostic marker for cardiovascular events in patients with diabetes and end-stage renal disease. ADMA, an endogenous endothelial nitric oxide synthase (NOS3) inhibitor, is selectively metabolized by dimethylarginine dimethylaminohydrolase (DDAH). Low DDAH levels have been associated with cardiac and renal dysfunction, but its effects on DN are unknown. We hypothesized that enhanced renal DDAH-1 expression would improve DN by reducing ADMA and restoring NOS3 levels. DBA/2J mice injected with multiple low doses of vehicle or streptozotocin were subsequently injected intrarenally with adenovirus expressing DDAH-1 (Ad-h-DDAH-1) or vector control [Ad-green fluorescent protein (GFP)], and mice were followed for 6 wk. Diabetes was associated with increased kidney ADMA and reduced kidney DDAH activity and DDAH-1 expression but had no effect on kidney DDAH-2 expression. Ad-GFP-treated diabetic mice showed significant increases in albuminuria, histological changes, glomerular macrophage recruitment, inflammatory cytokine and fibrotic markers, kidney ADMA levels, and urinary thiobarbituric acid reactive substances excretion as an indicator of oxidative stress, along with a significant reduction in kidney DDAH activity and kidney NOS3 mRNA compared with normal mice. In contrast, Ad-h-DDAH-1 treatment of diabetic mice reversed these effects. These data indicate, for the first time, that DDAH-1 mediates renal tissue protection in DN via the ADMA-NOS3-interaction. Enhanced renal DDAH-1 activity could be a novel therapeutic tool for treating patients with diabetes.

Increased urinary miR-196a level predicts the progression of renal injury in patients with diabetic nephropathy

2018 ◽  
Vol 35 (6) ◽  
pp. 1009-1016 ◽  
Author(s):  
Yu An ◽  
Changming Zhang ◽  
Feng Xu ◽  
Wei Li ◽  
Caihong Zeng ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Nephropathy ◽  
Renal Injury ◽  
Cox Regression ◽  
Interstitial Fibrosis ◽  
Glomerular Sclerosis ◽  
Tubular Atrophy ◽  
Cox Regression Analysis ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background Recent data suggest that miR-196a is predominantly expressed in the kidney and plays an inhibitory role in the progress of renal interstitial fibrosis (IF). However, the predictive value of miR-196a in diabetic nephropathy (DN) remains unknown. We validated the role of urinary miR-196a in the progression of renal injury in a cohort of patients with type 2 diabetes mellitus. Methods Our study included 209 patients with biopsy-proven DN. The mean follow-up time was 54.03 ± 32.94 months. Histological lesions were assessed using the pathological classification established by the Renal Pathology Society. Percentages of IF and tubular atrophy were assessed using the Aperio ScanScope system. We measured the correlation of urinary miR-196a with clinical and pathological parameters using the Spearman’s correlation test. The influence of urinary miR-196a on renal outcomes was assessed using Cox regression analysis. Results Urinary miR-196a levels correlated positively with proteinuria (ρ = 0.385, P &lt; 0.001), duration of diabetes mellitus (ρ = 0.255, P &lt; 0.001) and systolic blood pressure (ρ = 0.267, P &lt; 0.001). The baseline estimated glomerular filtration rate (eGFR) and hemoglobin level showed a negative correlation with urinary miR-196a (ρ = −0.247, P &lt; 0.001 and ρ = −0.236, P = 0.001, respectively). Pathologically, urinary miR-196a levels correlated with glomerular sclerosis and IF in patients with DN. Urinary miR-196a was significantly associated with progression to end-stage renal disease [hazard ratio (HR) 2.03, P &lt; 0.001] and a 40% reduction of baseline eGFR (HR 1.75, P = 0.001), independent of age, gender, body mass index, mean arterial pressure and hemoglobinA1c level. However, urinary miR-196a did not improve predictive power to proteinuria and eGFR in DN patients. Conclusions Increased urinary miR-196a was significantly associated with the progression of renal injury and might be a noninvasive prognostic marker of renal fibrosis in DN patients.

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

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
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.

MO479BLOOD PRESSURE CONTROL AND OUTCOMES IN DIABETIC RENAL DISEASE : EVIDENCE FROM A TUNISIAN COHORT

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Boukhtioua Mariem ◽  
Mami Ikram ◽  
Tlili Syrine ◽  
Ghabi Hiba ◽  
Hela Jbali ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Diabetic Nephropathy ◽  
Renal Disease ◽  
Urinary Albumin Excretion ◽  
Pressure Control ◽  
Urinary Albumin ◽  
Patients With Diabetes ◽  
Group B ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background and Aims Diabetic nephropathy (DN) is associated with a high incidence of cardiovascular morbidity and mortality. The relationship between hypertension and diabetic nephropathy is complex and blood pressure (BP) control is an important management strategy in the prevention of its onset and progression .The aim of this study was to determine whether blood pressure control delays the progression of DN and prevents macrovascular complications in patients with diabetes mellitus. Method Hypertension guidelines advocate treating systolic blood pressure to less than 130 mm Hg and diastolic blood pressure to less than 80 mmHg for patients with diabetes mellitus and overt nephropathy.The relationship between blood pressure and progression of nephropathy was studied in 120 diabetic and hypertensive patients with established diabetic nephropathy. We divided hypertensive patients with stage 1 to 3 CKD already treated with antihypertensive therapy into 2 groups: those with BP &lt; 130/80 mmHg were designated as Group A (n=66) and those with BP&gt; 130/80 as Group B (n=54). Serum creatinine level as well as urinary albumin excretion were measured at 3 months,6 months, one year,2 years and at last visit during follow-up.The GFR was calculated using the Modification of diet in renal disease formula.The kidney disease outcome was defined as time to end-stage renal disease. The cardiovascular outcome was defined as time to myocardial infarction, stroke,ischemic stroke, hospitalization for heart failure, or revascularization. Results During the mean follow up period of 33,8 ± 11,7 months, the primary end point of end-stage renal disease occured in 9 patients (7 patients in Group B versus 2 patients in groupe A) while 11 hypertensive patient experienced a cardiovascular event.  The decline rate in GFR was significantly more important in groupe B (p&lt;0,05). However, little difference existed between the two groups in urinary albumin excretion. Blood pressure control was not associated with improved cardiovascular outcomes when comparing the two groups. Conclusion The results of our study indicate that an uncontrolled hypertension is associated with a rapid progression of kidney impairment in diabetic patients with overt nephropathy but no relationship with the incidence of cradiovascular events was seen in our population.

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

2014 ◽  
Vol 307 (6) ◽  
pp. F686-F694 ◽  
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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