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.

scholarly journals The endothelial-to-mesenchymal transition and endothelial cilia in EPC-mediated postischemic kidney protection

2016 ◽  
Vol 310 (7) ◽  
pp. F679-F687 ◽  
Author(s):  
D. Patschan ◽  
K. Schwarze ◽  
E. Henze ◽  
S. Patschan ◽  
G. A. Müller
Keyword(s):  
Endothelial Cells ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Mesenchymal Transition ◽  
Peritubular Capillaries ◽  
Endothelial To Mesenchymal Transition ◽  
Actin Expression

Renal ischemia induces peritubular capillary rarefication and fibrosis, with the latter partly resulting from the endothelial-to-mesenchymal transition (EndoMT). Endothelial cilia transmit blood flow-associated forces into the cell. Early endothelial progenitor cells (eEPCs) have been shown to protect mice from acute kidney injury in the short term. The aim of the present study was to analyze midterm consequences of eEPC treatment in the context of endothelial cilia and the EndoMT. Male C57/Bl6N mice were subjected to unilateral renal ischemia postuninephrectomy. Syngeneic murine eEPCs were systemically injected at the time of reperfusion. Animals were investigated 1, 4, and 6 wk later. Cultured mature endothelial cells were exposed to a variable flow with versus without eEPC supernatant incubation. Systemically injected eEPCs reduced serum creatinine levels at week 1 (35 and 45 min) and week 4 (45 min). Interstitial fibrosis was significantly diminished by cell treatment at all time points as well. The EndoMT was less pronounced at week 4 (35 min) and week 6 (45 min). eEPC supernatant reduced α-smooth muscle actin expression and α-tubulin abundance in flow-treated cultured mature endothelial cells, and percentages of cilium-positive cells increased. The loss of peritubular capillaries was prevented by eEPCs. Intrarenal endothelial α-tubulin decreased postischemia and was further reduced by eEPC administration. We conclude that eEPCs are capable of reorganizing the endothelial cytoskeleton in an indirect manner, ultimately resulting in stabilization of the endothelial ciliome. The investigation indicates an antimesenchymal role of endothelial cilia in the process of postischemic tissue fibrosis/EndoMT.

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.

Microscopic Polyangiitis: New Insights into Pathogenesis, Clinical Features and Therapy

2018 ◽  
Vol 39 (04) ◽  
pp. 459-464 ◽  
Author(s):  
Alexandre Karras
Keyword(s):  
Microscopic Polyangiitis ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Antineutrophil Cytoplasmic Antibody ◽  
Cause Of Deaths ◽  
Optimal Maintenance ◽  
General Signs ◽  
Rapidly Progressive Renal Failure ◽  
Stage Renal Disease ◽  
End Stage

AbstractMicroscopic polyangiitis (MPA) is one of the main clinical presentations of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Although the disease is defined by clinical and pathological criteria, the anti-myeloperoxidase (MPO) specificity of ANCAs is observed in almost 80% of MPA patients. The direct pathogenic role of anti-MPO antibodies has been proven in animal models, in which the disease was transmitted by transfer of anti-MPO antibodies or anti-MPO–specific splenocytes. The most frequently affected organs in this disease are the kidneys and the lungs. Necrotizing and crescentic glomerulonephritis can be revealed by rapidly progressive renal failure, but kidney injury can be more slowly progressive and lead to end-stage renal disease without major extrarenal manifestations. The most frequent pulmonary manifestation is diffuse alveolar hemorrhage, but some patients may present with chronic interstitial fibrosis leading to respiratory failure. General signs such as fever and weight loss, muscular and articular symptoms, peripheral neuropathy, and cutaneous involvement may also reveal the disease. Although the relapse rate is quite low after induction of remission, 5-year mortality is 25%, with even higher mortality rates in older patients (> 65 years old), or those with significant kidney dysfunction. Iatrogenic causes (particularly infections) are an important cause of deaths in these vulnerable patients. Future studies are warranted to determine the optimal maintenance immunosuppressive regimen to minimize side effects of immunosuppression.

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 < 0.001), duration of diabetes mellitus (ρ = 0.255, P < 0.001) and systolic blood pressure (ρ = 0.267, P < 0.001). The baseline estimated glomerular filtration rate (eGFR) and hemoglobin level showed a negative correlation with urinary miR-196a (ρ = −0.247, P < 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 < 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 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.

scholarly journals Macrophage Phenotype and Fibrosis in Diabetic Nephropathy

2020 ◽  
Vol 21 (8) ◽  
pp. 2806 ◽  
Author(s):  
Priscila Calle ◽  
Georgina Hotter
Keyword(s):  
Diabetic Nephropathy ◽  
Interstitial Fibrosis ◽  
Vascular Dysfunction ◽  
Inflammatory Cells ◽  
Macrophage Phenotype ◽  
Progressive Decline ◽  
Potential Factors ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease globally. The primary initiating mechanism in DN is hyperglycemia-induced vascular dysfunction, but its progression is due to different pathological mechanisms, including oxidative stress, inflammatory cells infiltration, inflammation and fibrosis. Macrophages (Mφ) accumulation in kidneys correlates strongly with serum creatinine, interstitial myofibroblast accumulation and interstitial fibrosis scores. However, whether or not Mφ polarization is involved in the progression of DN has not been adequately defined. The prevalence of the different phenotypes during the course of DN, the existence of hybrid phenotypes and the plasticity of these cells depending of the environment have led to inconclusive results. In the same sense the role of the different macrophage phenotype in fibrosis associated or not to DN warrants additional investigation into Mφ polarization and its role in fibrosis. Due to the association between fibrosis and the progressive decline of renal function in DN, and the role of the different phenotypes of Mφ in fibrosis, in this review we examine the role of macrophage phenotype control in DN and highlight the potential factors contributing to phenotype change and injury or repair in DN.

SIRT1: Mechanism and Protective in Diabetic Nephropathy

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.

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.

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