scholarly journals AMPK agonist alleviate renal tubulointerstitial fibrosis via activating mitophagy in high fat and streptozotocin induced diabetic mice

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Ya-chun Han ◽  
Shi-qi Tang ◽  
Yu-ting Liu ◽  
Ai-mei Li ◽  
Ming Zhan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Renal Tissue ◽  
Tubulointerstitial Fibrosis ◽  
Renal Tubular Cell ◽  
Pathological Feature ◽  
Diabetic Mice ◽  
High Fat ◽  
Compound C ◽  
Renal Tubulointerstitial Fibrosis ◽  
Renal Tubular

AbstractRenal tubulointerstitial fibrosis was a crucial pathological feature of diabetic nephropathy (DN), and renal tubular injury might associate with abnormal mitophagy. In this study, we investigated the effects and molecular mechanisms of AMPK agonist metformin on mitophagy and cellular injury in renal tubular cell under diabetic condition. The high fat diet (HFD) and streptozotocin (STZ)-induced type 2 diabetic mice model and HK-2 cells were used in this study. Metformin was administered in the drinking water (200 mg/kg/d) for 24 weeks. Renal tubulointerstitial lesions, oxidative stress and some indicators of mitophagy (e.g., LC3II, Pink1, and Parkin) were examined both in renal tissue and HK-2 cells. Additionally, compound C (an AMPK inhibitor) and Pink1 siRNA were applied to explore the molecular regulation mechanism of metformin on mitophagy. We found that the expression of p-AMPK, Pink1, Parkin, LC3II, and Atg5 in renal tissue of diabetic mice was decreased obviously. Metformin reduced the levels of serum creatinine, urine protein, and attenuated renal oxidative injury and fibrosis in HFD/STZ induced diabetic mice. In addition, Metformin reversed mitophagy dysfunction and the over-expression of NLRP3. In vitro pretreatment of HK-2 cells with AMPK inhibitor compound C or Pink1 siRNA negated the beneficial effects of metformin. Furthermore, we noted that metformin activated p-AMPK and promoted the translocation of Pink1 from the cytoplasm to mitochondria, then promoted the occurrence of mitophagy in HK-2 cells under HG/HFA ambience. Our results suggested for the first time that AMPK agonist metformin ameliorated renal oxidative stress and tubulointerstitial fibrosis in HFD/STZ-induced diabetic mice via activating mitophagy through a p-AMPK-Pink1-Parkin pathway.

scholarly journals HSP72 attenuates renal tubular cell apoptosis and interstitial fibrosis in obstructive nephropathy

2008 ◽  
Vol 295 (1) ◽  
pp. F202-F214 ◽  
Author(s):  
Haiping Mao ◽  
Zhilian Li ◽  
Yi Zhou ◽  
Zhijian Li ◽  
Shougang Zhuang ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Tubular Cell ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Renal Tubular Cell ◽  
Tubular Epithelium ◽  
Renal Tubulointerstitial Fibrosis ◽  
Renal Tubular ◽  
Tgf Β1

Although heat shock protein 72 kDa (HSP72) protects tubular epithelium from a variety of acute insults, its role in chronic renal injury and fibrosis is poorly characterized. In this study, we tested the hypothesis that HSP72 reduces apoptosis and epithelial-to-mesenchymal transition (EMT), important contributors to tubular cell injury in vitro and in vivo. In rats, orally administered geranylgeranylacetone (GGA), an agent that selectively induces HSP72, markedly reduced both apoptosis and cell proliferation in tubular epithelium and decreased both interstitial fibroblast accumulation and collagen I deposition after unilateral ureteric obstruction, a model of chronic renal tubulointerstitial fibrosis and dysfunction. In cultured renal NRK52E cells, exposure to TGF-β1 induced EMT and apoptosis, major causes of renal fibrosis and tubular atrophy, respectively. Exposure to a pan-caspase inhibitor (ZVAD-FMK) prevented TGF-β1-induced apoptosis but did not reduce EMT. In contrast, selective HSP72 expression in vitro inhibited EMT caused by TGF-β1 as indicated by preserving the E-cadherin expression level and α-smooth muscle actin induction. Small interfering RNA directed against HSP72 blocked the cytoprotective effects of HSP72 overexpression on EMT in TGF-β1-exposed cells. Taken together, our data indicate that HSP72 ameliorates renal tubulointerstitial fibrosis in obstructive nephropathy by inhibiting both renal tubular epithelial cell apoptosis and EMT.

Reduction of oxidative stress during recovery accelerates normalization of primary cilia length that is altered after ischemic injury in murine kidneys

2013 ◽  
Vol 304 (10) ◽  
pp. F1283-F1294 ◽  
Author(s):  
Jee In Kim ◽  
Jinu Kim ◽  
Hee-Seong Jang ◽  
Mi Ra Noh ◽  
Joshua H. Lipschutz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Primary Cilium ◽  
Primary Cilia ◽  
Mdck Cells ◽  
Reactive Oxygen ◽  
Renal Tubular Cell ◽  
Oxygen Species ◽  
Renal Tubular ◽  
Cilium Length

The primary cilium is a microtubule-based nonmotile organelle that extends from the surface of cells, including renal tubular cells. Here, we investigated the alteration of primary cilium length during epithelial cell injury and repair, following ischemia/reperfusion (I/R) insult, and the role of reactive oxygen species in this alteration. Thirty minutes of bilateral renal ischemia induced severe renal tubular cell damage and an increase of plasma creatinine (PCr) concentration. Between 8 and 16 days following the ischemia, the increased PCr returned to normal range, although without complete histological restoration. Compared with the primary cilium length in normal kidney tubule cells, the length was shortened 4 h and 1 day following ischemia, increased over normal 8 days after ischemia, and then returned to near normal 16 days following ischemia. In the urine of I/R-subjected mice, acetylated tubulin was detected. The cilium length of proliferating cells was shorter than that in nonproliferating cells. Mature cells had shorter cilia than differentiating cells. Treatment with Mn(III) tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP), an antioxidant, during the recovery of damaged kidneys accelerated normalization of cilia length concomitant with a decrease of oxidative stress and morphological recovery in the kidney. In the Madin-Darby canine kidney (MDCK) cells, H2O2 treatment caused released ciliary fragment into medium, and MnTMPyP inhibited the deciliation. The ERK inhibitor U0126 inhibited elongation of cilia in normal and MDCK cells recovering from H2O2 stress. Taken together, our results suggest that primary cilia length reflects cell proliferation and the length of primary cilium is regulated, at least, in part, by reactive oxygen species through ERK.

Silymarin Regulates Tgf-β1/Smad3 Signaling Pathway and Improves Renal Tubular Interstitial Fibrosis Caused by Obstructive Nephropathy

2021 ◽  
Vol 19 (4) ◽  
pp. 508-513
Author(s):  
Jinhao Wu ◽  
Chao Huang ◽  
Gang Kan ◽  
Hanyu Xiao ◽  
Xiaoping Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Interstitial Fibrosis ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Therapeutic Drugs ◽  
Renal Tubulointerstitial Fibrosis ◽  
Liver And Kidney ◽  
Renal Tubular ◽  
Antioxidant Effects ◽  
Tgf Β1

Obstructive nephropathy often leads to renal tubulointerstitial fibrosis. Understanding of the pathogenesis of renal tubulointerstitial fibrosis caused by obstructive nephropathy is crucial to the development of effective therapeutic drugs to improve the prognosis of the patients. Silymarin, a polyphenolic flavonoid extracted from plants, has been shown to exhibit antiinflammatory and antioxidant effects ameliorating liver and kidney damage. However, the effect of silymarin on renal fibrosis in obstructive nephropathy remains to be explored. In this study, we found silymarin improved interstitial fibrosis and apoptosis induced by TGF-β1 and ameliorated oxidative damage. Our data further confirmed that silymarin regulates the TGF-β1/ Smad3 signaling pathway, and therefore improves renal tubular interstitial fibrosis caused by obstructive nephropathy.

scholarly journals Active Vitamin D and Vitamin D Receptor Help Prevent High Glucose Induced Oxidative Stress of Renal Tubular Cells via AKT/UCP2 Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
XiaoJuan Zhu ◽  
ShengHua Wu ◽  
HanCheng Guo
Keyword(s):  
Oxidative Stress ◽  
Vitamin D ◽  
Flow Cytometry ◽  
High Glucose ◽  
Mitochondrial Membrane ◽  
Renal Tubular Cell ◽  
Active Vitamin ◽  
Akt Inhibitor ◽  
Renal Tubular ◽  
Hk2 Cells

Background. It has been documented that vitamin D supplementation showed an improvement of symptoms of diabetic nephropathy; however, the underlying mechanisms remain unknown. We here tested the hypothesis that active vitamin D is able to up-regulate AKT/UCP2 signaling to alleviate oxidative stress of renal tubular cell line HK2.Methods. There are eight groups in the present study: normal glucose, osmotic control (5.5 mmol/L D-glucose+24.5 mmol/L D-mannitol), NAC control (30 mmol/L D-glucose + 1.0 mmol/L N-Methylcysteine), high glucose, high glucose+VD, high glucose (HG)+VD+siVDR, HG+VD+AKT inhibitor (AI), and high glucose+VD+UCP2 inhibitor (Gelipin). Concentration of superoxide dismutase (SOD) and malondialdehyde (MDA) was analyzed by ELISA. Reactive oxygen species (ROS), mitochondrial membrane potential and apoptosis were measured by flow cytometry. JC-1 was evaluated by flow cytometry. The presence of VDR, AKT, and UCP2 in HK cells was assessed using RT-PCR and western blot analyses.Results. VD administration significantly upregulated the SOD activation and downregulated MDA levels compared to HG group. siVDR, AKT inhibitor, and UCP2 inhibitor significantly suppressed the activation of SOD and increased the expression of MDA compared to VD group. ROS generation and apoptosis of HK2 cells in HG+VD group were significantly lower than those in HG, HG+VD+siVDR, HG+VD+AI, and HG+VD+Gelipin group. ΔΨm in HG+VD group was obviously higher than those in HG, HG+VD+siVDR, HG+VD+AI, and HG+VD+Gelipin group. Decreased mRNA and protein levels of VDR, p-AKT, and UCP2 were observed in HG+VD+siVDR, HG+VD+AI, and HG+VD+Gelipin group compared to those in HG+VD group.Conclusions. siVDR, AKT inhibitor, and UCP2 inhibitor elevated the ROS and apoptosis of HK2 cells while attenuating the mitochondrial membrane potential, suggesting that vitamin D protects renal tubular cell from high glucose by AKT/UCP2 signaling pathway.

Peroxiredoxin 1 inhibits the oxidative stress induced apoptosis in renal tubulointerstitial fibrosis

Nephrology ◽  
2015 ◽  
Vol 20 (11) ◽  
pp. 832-842 ◽  
Author(s):  
Wenjuan Mei ◽  
Zhangzhe Peng ◽  
Miaomiao Lu ◽  
Chunyan Liu ◽  
Zhenghao Deng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Tubulointerstitial Fibrosis ◽  
Peroxiredoxin 1 ◽  
Renal Tubulointerstitial Fibrosis ◽  
Induced Apoptosis

scholarly journals Ameliorative Effect of Hexane Extract ofPhalaris canariensison High Fat Diet-Induced Obese and Streptozotocin-Induced Diabetic Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Rosa Martha Perez Gutierrez ◽  
Diana Madrigales Ahuatzi ◽  
Maria del Carmen Horcacitas ◽  
Efren Garcia Baez ◽  
Teresa Cruz Victoria ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Body Weight ◽  
High Fat Diet ◽  
Serum Insulin ◽  
Body Weight Loss ◽  
Insulin Level ◽  
Hexane Extract ◽  
Diabetic Mice ◽  
High Fat ◽  
Obesity And Diabetes

Obesity is one of the major factors to increase various disorders like diabetes. The present paper emphasizes study related to the antiobesity effect ofPhalaris canariensisseeds hexane extract (Al-H) in high-fat diet- (HFD-) induced obese CD1 mice and in streptozotocin-induced mild diabetic (MD) and severely diabetic (SD) mice.AL-H was orally administered to MD and SD mice at a dose of 400 mg/kg once a day for 30 days, and a set of biochemical parameters were studied: glucose, cholesterol, triglycerides, lipid peroxidation, liver and muscle glycogen, ALP, SGOT, SGPT, glucose-6-phosphatase, glucokinase, hexokinase, SOD, CAT, GSH, GPX activities, and the effect on insulin level. HS-H significantly reduced the intake of food and water and body weight loss as well as levels of blood glucose, serum cholesterol, triglyceride, lipoprotein, oxidative stress, showed a protective hepatic effect, and increased HDL-cholesterol, serum insulin in diabetic mice. The mice fed on the high-fat diet and treated with AL-H showed inhibitory activity on the lipid metabolism decreasing body weight and weight of the liver and visceral adipose tissues and cholesterol and triglycerides in the liver. We conclude that AL-H can efficiently reduce serum glucose and inhibit insulin resistance, lipid abnormalities, and oxidative stress in MD and SD mice. Our results demonstrate an antiobesity effect reducing lipid droplet accumulation in the liver, indicating that its therapeutic properties may be due to the interaction plant components soluble in the hexane extract, with any of the multiple targets involved in obesity and diabetes pathogenesis.

scholarly journals Fluorofenidone Alleviates Renal Fibrosis by Inhibiting Necroptosis Through RIPK3/MLKL Pathway

2020 ◽  
Vol 11 ◽  
Author(s):  
Qin Dai ◽  
Yan Zhang ◽  
Xiaohua Liao ◽  
Yupeng Jiang ◽  
Xin Lv ◽  
...  
Keyword(s):  
Cell Death ◽  
Renal Fibrosis ◽  
Tissue Injury ◽  
Tubulointerstitial Fibrosis ◽  
Sterile Inflammation ◽  
Tubular Damage ◽  
Monocyte Chemoattractant Protein 1 ◽  
Renal Tubulointerstitial Fibrosis ◽  
Tnf Α ◽  
Renal Tubular

Cell death and sterile inflammation are major mechanisms of renal fibrosis, which eventually develop into end-stage renal disease. “Necroptosis” is a type of caspase-independent regulated cell death, and sterile inflammatory response caused by tissue injury is strongly related to necrosis. Fluorofenidone (AKF-PD) is a novel compound shown to ameliorate renal fibrosis and associated inflammation. We investigated whether AKF-PD could alleviate renal fibrosis by inhibiting necroptosis. Unilateral ureteral obstruction (UUO) was used to induce renal tubulointerstitial fibrosis in C57BL/6J mice. AKF-PD (500 mg/kg) or necrostatin-1 (Nec-1; 1.65 mg/kg) was administered simultaneously for 3 and 7 days. Obstructed kidneys and serum were harvested after euthanasia. AKF-PD and Nec-1 ameliorated renal tubular damage, inflammatory-cell infiltration, and collagen deposition, and the expression of proinflammatory factors (interlukin-1β, tumor necrosis factor [TNF]-α) and chemokines (monocyte chemoattractant protein-1) decreased. AKF-PD or Nec-1 treatment protected renal tubular epithelial cells from necrosis and reduced the release of lactate dehydrogenase in serum. Simultaneously, production of receptor-interacting protein kinase (RIPK)3 and mixed lineage kinase domain-like protein (MLKL) was also reduced 3 and 7 days after UUO. AKF-PD and Nec-1 significantly decreased the percentage of cell necrosis, inhibiting the phosphorylation of MLKL and RIPK3 in TNF-α- and Z-VAD–stimulated human proximal tubular epithelial (HK-2) cells. In conclusion, AKF-PD and Nec-1 have effective anti-inflammatory and antifibrotic activity in UUO-induced renal tubulointerstitial fibrosis, potentially mediated by the RIPK3/MLKL pathway.

scholarly journals Connexin 43 prevents the progression of diabetic renal tubulointerstitial fibrosis by regulating the SIRT1-HIF-1α signaling pathway

2020 ◽  
Vol 134 (13) ◽  
pp. 1573-1592
Author(s):  
Xiaohong Sun ◽  
Kaipeng Huang ◽  
Xiao Haiming ◽  
Zeyuan Lin ◽  
Yan Yang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Connexin 43 ◽  
Epithelial To Mesenchymal Transition ◽  
Hypoxia Inducible Factor ◽  
Pathological Process ◽  
Tubulointerstitial Fibrosis ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Renal Tubulointerstitial Fibrosis ◽  
Renal Tubular

Abstract Hyperglycemia-induced renal epithelial-to-mesenchymal transition (EMT) is a key pathological factor in diabetic renal tubulointerstitial fibrosis (RIF). Our previous studies have shown that connexin 43 (Cx43) activation attenuated the development of diabetic renal fibrosis. However, whether Cx43 regulates the EMT of renal tubular epithelial cells (TECs) and the pathological process of RIF under the diabetic conditions remains to be elucidated. In the present study, we identified that Cx43 protein expression was down-regulated in the kidney tissues of db/db mice as well as in high glucose (HG)-induced NRK-52E cells. Overexpression of Cx43 improved renal function in db/db spontaneous diabetic model mice, increased SIRT1 levels, decreased hypoxia-inducible factor (HIF)-1α expression, and reduced production of EMT markers and extracellular matrix (ECM) components. Additionally, Cx43 overexpression inhibited the EMT process and reduced the expression of ECM components such as fibronectin (FN), Collagen I, and Collagen IV in HG-induced NRK-52E cells, whereas Cx43 deficiency had the opposite effects. Mechanistically, Cx43 in a carboxyl-terminal signal transduction-dependent manner could up-regulate SIRT1 expression and enhance SIRT1-dependent deacetylation of HIF-1α to reduce HIF-1α activity, which eventually ameliorated renal EMT and diabetic RIF. Our study indicates the essential role of Cx43 in regulating renal EMT and diabetic RIF via regulating the SIRT1-HIF-1α signaling pathway and provides an experimental basis for Cx43 as a potential target for diabetic nephropathy (DN).

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