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 CDKN2B-AS1 participates in high glucose-induced apoptosis and fibrosis via NOTCH2 through functioning as a miR-98-5p decoy in human podocytes and renal tubular cells

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Min Xiao ◽  
Shoujun Bai ◽  
Jing Chen ◽  
Yaxi Li ◽  
Shu Zhang ◽  
...  
Keyword(s):  
High Glucose ◽  
Kinase Inhibitor ◽  
Luciferase Reporter ◽  
Tubular Cells ◽  
Protein Levels ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Induced Apoptosis ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background Diabetic nephropathy (DN) is the most common causes of end-stage renal disease. Long non-coding RNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) is connected with the development of DN, but the role of CDKN2B-AS1 in DN has not been entirely elucidated. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to measure CDKN2B-AS1 and miR-98-5p levels. Cell viability, proliferation, and apoptosis were analyzed with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) or flow cytometry assays. Protein levels were measured by western blotting. The relationship between CDKN2B-AS1 or notch homolog 2 (NOTCH2) and miR-98-5p was verified via dual-luciferase reporter assay. Results CDKN2B-AS1 and NOTCH2 were upregulated in the serum of DN patients and high glucose-disposed human podocytes (HPCs) and human renal tubular cells (HK-2), whereas miR-98-5p was downregulated. High glucose repressed viability and accelerated apoptosis of HPCs and HK-2 cells. CDKN2B-AS1 knockdown impaired high glucose-induced apoptosis and fibrosis of HPCs and HK-2 cells. Mechanistically, CDKN2B-AS1 sponged miR-98-5p to regulate NOTCH2 expression. Also, CDKN2B-AS1 inhibition-mediated effects on apoptosis and fibrosis of high glucose-disposed HPCs and HK-2 cells were weakened by miR-98-5p inhibitor. Also, NOTCH2 knockdown partly reversed miR-98-5p inhibitor-mediated impacts on apoptosis and fibrosis of high glucose-disposed HPCs and HK-2 cells. Conclusion High glucose-induced CDKN2B-AS1 promoted apoptosis and fibrosis via the TGF-β1 signaling mediated by the miR-98-5p/NOTCH2 axis in HPCs and HK-2 cells.

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.

scholarly journals Role of Nutrient-Sensing Signals in the Pathogenesis of Diabetic Nephropathy

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Shinji Kume ◽  
Daisuke Koya ◽  
Takashi Uzu ◽  
Hiroshi Maegawa
Keyword(s):  
Diabetic Nephropathy ◽  
Therapeutic Potential ◽  
Nutrient Sensing ◽  
Tubular Cells ◽  
New Findings ◽  
Proximal Tubular ◽  
Stage Renal Disease ◽  
End Stage ◽  
Autophagy Activity

Diabetic nephropathy is the leading cause of end-stage renal disease worldwide. The multipronged drug approach still fails to fully prevent the onset and progression of diabetic nephropathy. Therefore, a new therapeutic target to improve the prognosis of diabetic nephropathy is urgently required. Nutrient-sensing signals and their related intracellular machinery have evolved to combat prolonged periods of starvation in mammals; and these systems are conserved in the kidney. Recent studies have suggested that the activity of three nutrient-sensing signals, mTORC1, AMPK, and Sirt1, is altered in the diabetic kidney. Furthermore, autophagy activity, which is regulated by the above-mentioned nutrient-sensing signals, is also altered in both podocytes and proximal tubular cells under diabetic conditions. Under diabetic conditions, an altered nutritional state owing to nutrient excess may disturb cellular homeostasis regulated by nutrient-responsible systems, leading to exacerbation of organelle dysfunction and diabetic nephropathy. In this review, we discuss new findings showing relationships between nutrient-sensing signals, autophagy, and diabetic nephropathy and suggest the therapeutic potential of nutrient-sensing signals in diabetic nephropathy.

scholarly journals Small Heat Shock Protein Beta-1 (HSPB1) Is Upregulated and Regulates Autophagy and Apoptosis of Renal Tubular Cells in Acute Kidney Injury

PLoS ONE ◽  
2015 ◽  
Vol 10 (5) ◽  
pp. e0126229 ◽  
Author(s):  
Tatsuki Matsumoto ◽  
Madoka Urushido ◽  
Haruna Ide ◽  
Masayuki Ishihara ◽  
Kazu Hamada-Ode ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Kidney Injury ◽  
Small Heat Shock Protein ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

scholarly journals PTEN alleviates maladaptive repair of renal tubular epithelial cells by restoring CHMP2A-mediated phagosome closure

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Huizhen Wang ◽  
Yifan Wang ◽  
Xin Wang ◽  
Huimi Huang ◽  
Jingfu Bao ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Renal Fibrosis ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Mass Spectrometry Analysis ◽  
Acute Injury ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

AbstractPhosphatase and Tensin Homolog on chromosome Ten (PTEN) has emerged as a key protein that governs the response to kidney injury. Notably, renal adaptive repair is important for preventing acute kidney injury (AKI) to chronic kidney disease (CKD) transition. To test the role of PTEN in renal repair after acute injury, we constructed a mouse model that overexpresses PTEN in renal proximal tubular cells (RPTC) by crossing PTENfl-stop-fl mice with Ggt1-Cre mice. Mass spectrometry-based proteomics was performed after subjecting these mice to ischemia/reperfusion (I/R). We found that PTEN was downregulated in renal tubular cells in mice and cultured HK-2 cells subjected to renal maladaptive repair induced by I/R. Renal expression of PTEN negatively correlated with NGAL and fibrotic markers. RPTC-specific PTEN overexpression relieved I/R-induced maladaptive repair, as indicated by alleviative tubular cell damage, apoptosis, and subsequent renal fibrosis. Mass spectrometry analysis revealed that differentially expressed proteins in RPTC-specific PTEN overexpression mice subjected to I/R were significantly enriched in phagosome, PI3K/Akt, and HIF-1 signaling pathway and found significant upregulation of CHMP2A, an autophagy-related protein. PTEN deficiency downregulated CHMP2A and inhibited phagosome closure and autolysosome formation, which aggravated cell injury and apoptosis after I/R. PTEN overexpression had the opposite effect. Notably, the beneficial effect of PTEN overexpression on autophagy flux and cell damage was abolished when CHMP2A was silenced. Collectively, our study suggests that PTEN relieved renal maladaptive repair in terms of cell damage, apoptosis, and renal fibrosis by upregulating CHMP2A-mediated phagosome closure, suggesting that PTEN/CHMP2A may serve as a novel therapeutic target for the AKI to CKD transition.

scholarly journals Novel Evidence of Acute Kidney Injury in COVID-19

2020 ◽  
Vol 9 (11) ◽  
pp. 3547
Author(s):  
Ti-I Chueh ◽  
Cai-Mei Zheng ◽  
Yi-Chou Hou ◽  
Kuo-Cheng Lu
Keyword(s):  
Acute Kidney Injury ◽  
Angiotensin Converting Enzyme ◽  
Kidney Injury ◽  
Host Cells ◽  
Current Evidence ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

The coronavirus 2019 (COVID-19) pandemic has caused a huge impact on health and economic issues. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes cellular damage by entry mediated by the angiotensin-converting enzyme 2 of the host cells and its conjugation with spike proteins of SARS-CoV-2. Beyond airway infection and acute respiratory distress syndrome, acute kidney injury is common in SARS-CoV-2-associated infection, and acute kidney injury (AKI) is predictive to multiorgan dysfunction in SARS-CoV-2 infection. Beyond the cytokine storm and hemodynamic instability, SARS-CoV-2 might directly induce kidney injury and cause histopathologic characteristics, including acute tubular necrosis, podocytopathy and microangiopathy. The expression of apparatus mediating SARS-CoV-2 entry, including angiotensin-converting enzyme 2, transmembrane protease serine 2 (TMPRSS2) and a disintegrin and metalloprotease 17 (ADAM17), within the renal tubular cells is highly associated with acute kidney injury mediated by SARS-CoV-2. Both entry from the luminal and basolateral sides of the renal tubular cells are the possible routes for COVID-19, and the microthrombi associated with severe sepsis and the dysregulated renin–angiotensin–aldosterone system worsen further renal injury in SARS-CoV-2-associated AKI. In the podocytes of the glomerulus, injured podocyte expressed CD147, which mediated the entry of SARS-CoV-2 and worsen further foot process effacement, which would worsen proteinuria, and the chronic hazard induced by SARS-CoV-2-mediated kidney injury is still unknown. Therefore, the aim of the review is to summarize current evidence on SARS-CoV-2-associated AKI and the possible pathogenesis directly by SARS-CoV-2.

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

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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