scholarly journals Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

2018 ◽  
Vol 51 (4) ◽  
pp. 1778-1798 ◽  
Author(s):  
Yunfang Zhang ◽  
Junxia Feng ◽  
Qi Wang ◽  
Shili Zhao ◽  
Shen Yang ◽  
...  
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
Mitochondrial Dysfunction ◽  
Western Blotting ◽  
High Glucose ◽  
Renal Injury ◽  
Mitochondrial Fragmentation ◽  
Mitochondrial Potential ◽  
Mitochondrial Homeostasis ◽  
Mptp Opening

Background/Aims: Hyperglycaemia stress-induced renal injury is closely associated with mitochondrial dysfunction through poorly understood mechanisms. The aim of our study is to explore the upstream trigger and the downstream effector driving diabetic nephropathy via modulating mitochondrial homeostasis. Methods: A diabetic nephropathy model was generated in wild-type (WT) mice and MAP Kinase phosphatase 1 transgenic (MKP1-TG) mice using STZ injection. Cell experiments were conducted via high-glucose treatment in the human renal mesangial cell line (HRMC). MKP1 overexpression assay was carried out via adenovirus transfection. Renal function was evaluated via ELISA, western blotting, histopathological staining, and immunofluorescence. Mitochondrial function was determined via mitochondrial potential analysis, ROS detection, ATP measurement, mitochondrial permeability transition pore (mPTP) opening evaluation, and immunofluorescence for mitochondrial pro-apoptotic factors. Loss- and gain-of-function assays for mitochondrial fragmentation were performed using a pharmacological agonist and blocker. Western blotting and the pathway blocker were used to establish the signalling pathway in response to MKP1 overexpression in the presence of hyperglycaemia stress. Results: MKP1 was downregulated in the presence of chronic high-glucose stress in vivo and in vitro. However, MKP1 overexpression improved the metabolic parameters, enhanced glucose control, sustained renal function, attenuated kidney oxidative stress, inhibited the renal inflammation response, alleviated HRMC apoptosis, and repressed tubulointerstitial fibrosis. Molecular investigation found that MKP1 overexpression enhanced the resistance of HRMC to the hyperglycaemic injury by abolishing mitochondrial fragmentation. Hyperglycaemia-triggered mitochondrial fragmentation promoted mitochondrial dysfunction, as evidenced by decreased mitochondrial potential, elevated mitochondrial ROS production, increased pro-apoptotic factor leakage, augmented mPTP opening and activated caspase-9 apoptotic pathway. Interestingly, MKP1 overexpression strongly abrogated mitochondrial fragmentation and sustained mitochondrial homeostasis via inhibiting the JNK-CaMKII-Fis1 pathway. After re-activation of the JNK-CaMKII-Fis1 pathway, the beneficial effects of MKP1 overexpression on mitochondrial protection disappeared. Conclusion: Taken together, our data identified the protective role played by MKP1 in regulating diabetic renal injury via repressing mitochondrial fragmentation and inactivating the JNK-CaMKII-Fis1 pathway, which may pave the road to new therapeutic modalities for the treatment of diabetic nephropathy.

scholarly journals SIRT3 Facilitates Amniotic Fluid Stem Cells to Repair Diabetic Nephropathy Through Protecting Mitochondrial Homeostasis by Modulation of Mitophagy

2018 ◽  
Vol 46 (4) ◽  
pp. 1508-1524 ◽  
Author(s):  
Jianxun Feng ◽  
Chang Lu ◽  
Qin Dai ◽  
Junqin Sheng ◽  
Min Xu
Keyword(s):  
Stem Cells ◽  
Diabetic Nephropathy ◽  
Amniotic Fluid ◽  
Western Blotting ◽  
Mitochondrial Function ◽  
High Glucose ◽  
Function Analysis ◽  
Immunofluorescence Analysis ◽  
Amniotic Fluid Stem Cells ◽  
Cell Based Therapy

Background/Aims: Amniotic fluid stem cells (AFSCs) transplantation is a promising therapeutic strategy for diabetic nephropathy. Sirtuin3 (SIRT3) is a novel mitochondrial protective factor. In the present study, we aimed to investigate whether SIRT3 protects against hyperglycemia-induced AFSCs damage and enhances the therapeutic efficiency of AFSCs in diabetic nephropathy. Methods: To establish the diabetic nephropathy model, db/ db mice were used. AFSCs were obtained and transplanted into the kidney tissue of db/ db mice. Gain-of-function assay with SIRT3 overexpression was performed in AFSCs via adenoviral transfections (Ad/SIRT3). Cellular viability and apoptosis were measured via MTT, TUNEL assay and western blotting. Mitochondrial function was assessed via JC1 staining, mPTP opening assay, mitochondrial respiratory function analysis, and immunofluorescence analysis of cyt-c. Mitophagy was assessed via western blotting and immunofluorescence analysis. Renal histopathology and morphometric analysis were conducted via H&E, Masson and PASM staining. Kidney function was detected via ELISA assay, western blotting and qPCR. Results: SIRT3 was downregulated in AFSCs under high glucose stimulation, where its expression was positively correlated with AFSCs survival and proliferation. Regaining SIRT3 activated mitophagy protecting AFSCs against high glucose-induced apoptosis via preserving mitochondrial function. Transplanting SIRT3-overexpressing AFSCs in db/db mice improved the abnormalities in glucose metabolic parameters, including the levels of glucose, insulin, C-peptide, HbA1c and inflammatory markers. In addition, the engraftment of SIRT3-modified AFSCs also reversed renal function, decreased renal hypertrophy, and ameliorated renal histological changes in db/db mice. Functional studies confirmed that SIRT3-modified AFSCs promoted glomerulus survival and reduced renal fibrosis. Conclusion: Collectively, our results demonstrate that AFSCs may be a promising therapeutic treatment for ameliorating diabetes and the development of diabetic nephropathy and that the overexpression of SIRT3 in AFSCs may further increase the efficiency of stem cell-based therapy.

scholarly journals Buyang Huanwu Decoction protects against STZ-induced diabetic nephropathy by inhibiting TGF-β/Smad3 signaling-mediated renal fibrosis and inflammation

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Weifeng Wu ◽  
Yifan Wang ◽  
Haidi Li ◽  
Haiyong Chen ◽  
Jiangang Shen
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Renal Fibrosis ◽  
Mesangial Cells ◽  
Buyang Huanwu Decoction ◽  
Active Compounds ◽  
Renal Inflammation ◽  
Pas Staining ◽  
Tgf Β1

Abstract Background Buyang Huanwu Decoction (BHD) is a classical Chinese Medicine formula empirically used for diabetic nephropathy (DN). However, its therapeutic efficacies and the underlying mechanisms remain obscure. In our study, we aim to evaluate the renoprotective effect of BHD on a streptozotocin (STZ)-induced diabetic nephropathy mouse model and explore the potential underlying mechanism in mouse mesangial cells (MCs) treated with high glucose in vitro, followed by screening the active compounds in BHD. Methods Mice were received 50 mg/kg streptozotocin (STZ) or citrate buffer intraperitoneally for 5 consecutive days. BHD was intragastrically administrated for 12 weeks starting from week 4 after the diabetes induction. The quality control and quantitative analysis of BHD were studied by high-performance liquid chromatography (HPLC). Renal function was evaluated by urinary albumin excretion (UAE) using ELISA. The mesangial matrix expansion and renal fibrosis were measured using periodic acid-schiff (PAS) staining and Masson Trichrome staining. Mouse mesangial cells (MCs) were employed to study molecular mechanisms. Results We found that the impaired renal function in diabetic nephropathy was significantly restored by BHD, as indicated by the decreased UAE without affecting the blood glucose level. Consistently, BHD markedly alleviated STZ-induced diabetic glomerulosclerosis and tubulointerstitial injury as shown by PAS staining, accompanied by a reduction of renal inflammation and fibrosis. Mechanistically, BHD inhibited the activation of TGF-β1/Smad3 and NF-κB signaling in diabetic nephropathy while suppressing Arkadia expression and restoring renal Smad7. We further found that calycosin-7-glucoside (CG) was one of the active compounds from BHD, which significantly suppressed high glucose-induced inflammation and fibrosis by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways in mesangial cells. Conclusion BHD could attenuate renal fibrosis and inflammation in STZ-induced diabetic kidneys via inhibiting TGF-β1/Smad3 and NF-κB signaling while suppressing the Arkadia and restoring renal Smad7. CG could be one of the active compounds in BHD to suppress renal inflammation and fibrosis in diabetic nephropathy.

scholarly journals A protective role of renalase in diabetic nephropathy

2020 ◽  
Vol 134 (1) ◽  
pp. 75-85 ◽  
Author(s):  
Jianyong Yin ◽  
Xuanchen Liu ◽  
Ting Zhao ◽  
Rulian Liang ◽  
Rui Wu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Knockout Mice ◽  
High Glucose ◽  
Renal Injury ◽  
Mesangial Cells ◽  
Therapeutic Potential ◽  
Genetically Engineered ◽  
Arterial Blood ◽  
Genetically Engineered Mouse Model

Abstract Renalase, a recently discovered secreted flavoprotein, exerts anti-apoptotic and anti-inflammatory effects against renal injury in acute and chronic animal models. However, whether Renalase elicits similar effects in the development of diabetic nephropathy (DN) remains unclear. The studies presented here tested the hypothesis that Renalase may play a key role in the development of DN and may have therapeutic potential for DN. Renalase expression was measured in human kidney biopsies with DN and in kidneys of db/db mice. The role of Renalase in the development of DN was examined using a genetically engineered mouse model: Renalase knockout mice with db/db background. The renoprotective effects of Renalase in DN was evaluated in db/db mice with Renalase overexpression. In addition, the effects of Renalase on high glucose-induced mesangial cells were investigated. Renalase was down-regulated in human diabetic kidneys and in kidneys of db/db mice compared with healthy controls or db/m mice. Renalase homozygous knockout increased arterial blood pressure significantly in db/db mice while heterozygous knockout did not. Renalase heterozygous knockout resulted in elevated albuminuria and increased renal mesangial expansion in db/db mice. Mesangial hypertrophy, renal inflammation, and pathological injury in diabetic Renalase heterozygous knockout mice were significantly exacerbated compared with wild-type littermates. Moreover, Renalase overexpression significantly ameliorated renal injury in db/db mice. Mechanistically, Renalase attenuated high glucose-induced profibrotic gene expression and p21 expression through inhibiting extracellular regulated protein kinases (ERK1/2). The present study suggested that Renalase protected against the progression of DN and might be a novel therapeutic target for the treatment of DN.

Grape seed procyanidin B2 protects podocytes from high glucose-induced mitochondrial dysfunction and apoptosis via the AMPK-SIRT1-PGC-1α axis in vitro

2016 ◽  
Vol 7 (2) ◽  
pp. 805-815 ◽  
Author(s):  
Xiaxia Cai ◽  
Lei Bao ◽  
Jinwei Ren ◽  
Yong Li ◽  
Zhaofeng Zhang
Keyword(s):  
Diabetic Nephropathy ◽  
Mitochondrial Dysfunction ◽  
High Glucose ◽  
Grape Seed ◽  
Protective Effects

Grape seed procyanidin B2 (GSPB2) was reported to have protective effects on diabetic nephropathy (DN) as a strong antioxidant.

scholarly journals Mitochondrial Dysfunction and Diabetic Nephropathy: Nontraditional Therapeutic Opportunities

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Ping Na Zhang ◽  
Meng Qi Zhou ◽  
Jing Guo ◽  
Hui Juan Zheng ◽  
Jingyi Tang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Mitochondrial Dysfunction ◽  
Therapeutic Strategy ◽  
Diabetic Complication ◽  
Therapeutic Interventions ◽  
Renal Diseases ◽  
Normal Kidney ◽  
Mitochondrial Homeostasis ◽  
Potential Value ◽  
Pharmacological Regulation

Diabetic nephropathy (DN) is a progressive microvascular diabetic complication. Growing evidence shows that persistent mitochondrial dysfunction contributes to the progression of renal diseases, including DN, as it alters mitochondrial homeostasis and, in turn, affects normal kidney function. Pharmacological regulation of mitochondrial networking is a promising therapeutic strategy for preventing and restoring renal function in DN. In this review, we have surveyed recent advances in elucidating the mitochondrial networking and signaling pathways in physiological and pathological contexts. Additionally, we have considered the contributions of nontraditional therapy that ameliorate mitochondrial dysfunction and discussed their molecular mechanism, highlighting the potential value of nontraditional therapies, such as herbal medicine and lifestyle interventions, in therapeutic interventions for DN. The generation of new insights using mitochondrial networking will facilitate further investigations on nontraditional therapies for DN.

scholarly journals NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

2018 ◽  
Vol 48 (4) ◽  
pp. 1675-1693 ◽  
Author(s):  
Junqin Sheng ◽  
Hongyan Li ◽  
Qin Dai ◽  
Chang Lu ◽  
Min Xu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Western Blotting ◽  
Mitochondrial Dynamics ◽  
Therapeutic Option ◽  
Mitochondrial Fission ◽  
Mitochondrial Oxidative Stress ◽  
Atp Production ◽  
Metabolism Disorder ◽  
P53 Signaling ◽  
Mptp Opening

Background/Aims: Disrupted mitochondrial dynamics, including excessive mitochondrial fission and mitophagy arrest, has been identified as a pathogenic factor in diabetic nephropathy (DN), although the upstream regulatory signal for mitochondrial fission activation and mitophagy arrest in the setting of DN remains unknown. Methods: Wild-type (WT) mice and NR4A1 knockout (NR4A1-KO) mice were used to establish a DN model. Mitochondrial fission and mitophagy were evaluated by western blotting and immunofluorescence. Mitochondrial function was assessed by JC-1 staining, the mPTP opening assay, immunofluorescence and western blotting. Renal histopathology and morphometric analyses were conducted via H&E, Masson and PASM staining. Kidney function was evaluated via ELISA, western blotting and qPCR. Results: In the present study, we found that nuclear receptor subfamily 4 group A member 1 (NR4A1) was actually activated by a chronic hyperglycemic stimulus. Higher NR4A1 expression was associated with glucose metabolism disorder, renal dysfunction, kidney hypertrophy, renal fibrosis, and glomerular apoptosis. At the molecular level, increased NR4A1 expression activated p53, and the latter selectively stimulated mitochondrial fission and inhibited mitophagy by modulating Mff and Parkin transcription. Excessive Mff-related mitochondrial fission caused mitochondrial oxidative stress, promoted mPTP opening, exacerbated proapoptotic protein leakage into the cytoplasm, and finally initiated mitochondria-dependent cellular apoptosis in the setting of diabetes. In addition, defective Parkin-mediated mitophagy repressed cellular ATP production and failed to correct the uncontrolled mitochondrial fission. However, NR4A1 knockdown interrupted the Mff-related mitochondrial fission and recused Parkin-mediated mitophagy, reducing the hyperglycemia-mediated mitochondrial damage and thus improving renal function. Conclusion: Overall, we have shown that NR4A1 functions as a novel malefactor in diabetic renal damage and operates by synchronously enhancing Mff-related mitochondrial fission and repressing Parkin-mediated mitophagy. Thus, finding strategies to regulate the balance of the NR4A1-p53 signaling pathway and mitochondrial homeostasis may be a therapeutic option for treating diabetic nephropathy in clinical practice.

Beyond proteinuria: VDR activation reduces renal inflammation in experimental diabetic nephropathy

2012 ◽  
Vol 302 (6) ◽  
pp. F647-F657 ◽  
Author(s):  
Maria-Dolores Sanchez-Niño ◽  
Milica Bozic ◽  
Elizabeth Córdoba-Lanús ◽  
Petya Valcheva ◽  
Olga Gracia ◽  
...  
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
Mrna Expression ◽  
Experimental Model ◽  
High Glucose ◽  
Glomerular Cell ◽  
Renal Inflammation ◽  
Matrix Deposition ◽  
Mediators Of Inflammation ◽  
Anti Inflammatory

Local inflammation is thought to contribute to the progression of diabetic nephropathy. The vitamin D receptor (VDR) activator paricalcitol has an antiproteinuric effect in human diabetic nephropathy at high doses. We have explored potential anti-inflammatory effects of VDR activator doses that do not modulate proteinuria in an experimental model of diabetic nephropathy to gain insights into potential benefits of VDR activators in those patients whose proteinuria is not decreased by this therapy. The effect of calcitriol and paricalcitol on renal function, albuminuria, and renal inflammation was explored in a rat experimental model of diabetes induced by streptozotocin. Modulation of the expression of mediators of inflammation by these drugs was explored in cultured podocytes. At the doses used, neither calcitriol nor paricalcitol significantly modified renal function or reduced albuminuria in experimental diabetes. However, both drugs reduced the total kidney mRNA expression of IL-6, monocyte chemoattractant protein (MCP)-1, and IL-18. Immunohistochemistry showed that calcitriol and paricalcitol reduced MCP-1 and IL-6 in podocytes and tubular cells as well as glomerular infiltration by macrophages, glomerular cell NF-κB activation, apoptosis, and extracellular matrix deposition. In cultured podocytes, paricalcitol and calcitriol at concentrations in the physiological and clinically significant range prevented the increase in MCP-1, IL-6, renin, and fibronectin mRNA expression and the secretion of MCP-1 to the culture media induced by high glucose. In conclusion, in experimental diabetic nephropathy VDR activation has local renal anti-inflammatory effects that can be observed even when proteinuria is not decreased. This may be ascribed to decreased inflammatory responses of intrinsic renal cells, including podocytes, to high glucose.

scholarly journals MicroRNA-146a-5p-modified human umbilical cord mesenchymal stem cells enhance protection against renal injury in diabetic nephropathy through facilitating M2 macrophage polarization by targeting TRAF6

2021 ◽  
Author(s):  
Yaqi Zhang ◽  
Xi Le ◽  
Shuo Zheng ◽  
Ke Zhang ◽  
Jing He ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Renal Function ◽  
Diabetic Nephropathy ◽  
High Throughput ◽  
Renal Injury ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Human Umbilical Cord ◽  
M2 Macrophage Polarization

Abstract Background Diabetic nephropathy (DN) is a severe complication of diabetes mellitus and a common cause of end-stage renal disease, but has no approved pharmacotherapy. Mesenchymal stem cells (MSCs) possess potent anti-inflammatory and immunomodulatory properties, which render them an attractive therapeutic tool for tissue damage and inflammation. Methods This study was designed to determine the protective effects and underlying mechanisms of human umbilical cord-derived MSCs (UC-MSCs) on streptozotocin-induced DN. Renal function and histological staining were used to evaluate kidney damage. RNA high-throughput sequencing on rat kidney and UCMSC-derived exosomes was used to identify the critical miRNAs. Co-cultivation of macrophage cell line and UC-MSCs-derived conditional medium was used to assess the involvement of macrophage polarization signaling. Results UC-MSC administration significantly improved renal function, reduced the local and systemic inflammatory cytokine levels, and attenuated inflammatory cell infiltration into the kidney tissue in DN rats. Moreover, UC-MSCs shifted macrophage polarization from a pro-inflammatory M1 to an antiinflammatory M2 phenotype. Mechanistically, miR-146a-5p was significantly downregulated and negatively correlated with renal injury in DN rats as determined through high-throughput RNA sequencing. Importantly, UC-MSCs-derived miR-146a-5p promoted M2 macrophage polarization by inhibiting TRAF6-STAT1 signaling pathway. Furthermore, miR-146a-5p modification in UC-MSCs enhanced the efficacy of anti-inflammation and renal function improvement. Conclusions Collectively, our findings demonstrate that UC-MSCs-derived miR-146a-5p have the potential to restore renal function in DN rats through facilitating M2 macrophage polarization by targeting TRAF6. It will pave the way for the use of UC-MSCs for therapeutic delivery of miRNAs targeted at kidney diseases.

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