scholarly journals The Role of Transcription Factor Ap1 in The Activation of Nrf2/ARE Pathway Through TET1 in Diabetic Nephropathy

2020 ◽  
Author(s):  
Yongshun Tan ◽  
Huaimin Cao ◽  
Qingfei Li ◽  
Jianjun Sun
Keyword(s):  
Transcription Factor ◽  
Diabetic Nephropathy ◽  
Renal Injury ◽  
Mesangial Cells ◽  
Diabetic Complication ◽  
Differentially Expressed ◽  
Inflammatory Factors ◽  
Enhanced Secretion ◽  
Differentially Expressed Mrna

Abstract Background: TET1 abnormal expression is related to tumorigenesis, but its role in diabetic nephropathy (DN), the most common diabetic complication, is unclear. We attempted to probe the possible mechanism of TET1 in DN.Methods: The DN rat model was established and verified by marker detection and histopathological observation. The in vitro model was established in human mesangial cells (HMCs) induced by high glucose (HG), and levels of IL-6, TNF-α, IV-C and FN were examined. The differentially expressed mRNAs were screened out by microarray analysis. The most differentially expressed mRNA (TET1) was overexpressed in DN rats and HMCs to evaluate inflammation, cell viability and apoptosis, biochemical indexes and renal injury. The upstream transcription factor of TET1 was verified, and overexpressed with/without TETE1 to access its role in inflammation and renal injury. The downstream gene and pathway were also verified.Results: TET1 was poorly expressed in DN rats and HG-HMCs. High expression of TET1 decreased biochemical indexes, and renal injury of DN rats, decreased the activity, fibrosis and inflammation of HG-HMCs. Ap1 inhibited TET1 expression, and enhanced secretion of inflammatory factors in HG-HMCs and renal injury in DN rats. TET1 overexpression inhibited the effect of Ap1 on DN. TET1 promoted the transcription of Nrf2. The Ap1/Tet1 axis mediated the Nrf2/ARE pathway activity.Conclusion: Ap1 inhibits TET1 expression and activates the Nrf2/ARE pathway in DN, thus aggravating inflammation and renal injury.

scholarly journals FBW7 Regulates the Autophagy Signal in Mesangial Cells Induced by High Glucose

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Chenlin Gao ◽  
Fang Fan ◽  
Jiao Chen ◽  
Yang Long ◽  
Shi Tang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Inflammatory Cytokines ◽  
High Glucose ◽  
Mesangial Cells ◽  
Negative Regulator ◽  
Inflammatory Factors ◽  
Gene Overexpression ◽  
F Box Protein ◽  
The Relationship

Aims. Abnormal regulation of autophagy participates in the development of diabetic nephropathy. mTOR is the most common negative regulator of the autophagy signaling pathway. FBW7 constitutes the SCF (Skp1–Cullin1–F-box protein) recognition subunit of E3 ubiquitin ligase, and mTOR is a substrate of FBW7 that can be modified by ubiquitination and be degraded via proteasomes. In this study, we explored the relationship between FBW7 and autophagy and examined the effects of FBW7 on the occurrence of diabetic nephropathy in vitro.Materials and Methods. We cultured mesangial cells induced by high glucose in vitro and used rapamycin as a specific mTOR inhibitor, performed FBW7 gene overexpression, and detected the expression of autophagy signal and inflammatory factors by WB, ELISA, RT-PCR, and immunofluorescence.Results. High glucose can downregulate the expression of FBW7 and activate mTOR signal, which leads to diminished autophagy in renal mesangial cells, as well as renal inflammatory cytokines and fibrotic factors. RAPA, as a specifically inhibitor of mTOR, can decrease inflammatory cytokines and fibrotic factors by inhibiting mTOR. Moreover, FBW7 gene overexpression can increase autophagy by inhibiting mTOR signal; at the same time, the inflammatory cytokines and fibrotic factors were decreased in mesangial cells.Conclusions. FBW7 was decreased in renal mesangial cells induced by high glucose, and FBW7 gene overexpression can increase autophagy by inhibiting mTOR signaling and ameliorate inflammation and fibrosis.

scholarly journals Dysregulation of miR-638 in diabetic nephropathy and its role in inflammatory response

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Mei Lin ◽  
Dan Song ◽  
Suo Zhang ◽  
Ping Li
Keyword(s):  
Diabetic Nephropathy ◽  
Inflammatory Responses ◽  
Mesangial Cells ◽  
Diagnostic Value ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Healthy Controls ◽  
Necrosis Factor Alpha

Abstract Background MicroRNA (miRNA) can be used as a biomarker for the early diagnosis of diabetic nephropathy (DN). The purpose of this study was to evaluate the diagnostic value of miR-638 in DN and to analyse its regulatory effect on inflammation. Methods This retrospective study involved 98 subjects, including non-diabetic healthy controls (n = 30), patients with type 2 diabetes (T2DM, n = 36) without complications and patients with DN (n = 32). After the anthropometric and biochemical evaluation, serum miR-638 levels were assessed by real-time reverse transcription-polymerase chain reaction (qRT-PCR). The levels of inflammatory cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor-alpha [TNF-α]) were detected using enzyme-linked immunosorbent assay. The Spearman correlations were used to analyze the correlation between miR-638 and urinary albumin excretion (UAE), estimated glomerular filtration rate (eGFR), and inflammatory factors. Furthermore, the receiver operating characteristic (ROC) curve was used to measure the diagnostic value of miR-638 in DN. Human mesangial cells (HMCs) were treated with normal glucose (NG, 5.5 mM glucose), high glucose (HG, 30 mM glucose), or high osmotic pressure solution (HO, 5.5 mM glucose + 24.5 mM mannitol) in vitro to simulate the hyperglycamic state in vivo. Subsequently, the HMCs were transfected with miR-638 mimics to regulate the level of miR-638 in the cells and detect its regulation on cell inflammation and proliferation. Results Compared with healthy controls and patients with T2DM, serum miR-638 in patients with DN was significantly lower. The reduced miR-638 expression has a significant diagnostic value, which can significantly distinguish patients with DN from healthy controls or patients with T2DM. Inflammatory factors were significantly upregulated in patients with DN and negatively correlated with miR-638 levels. In addition, miR-638 was negatively correlated with UAE and positively correlated with eGFR. HG decreased the level of miR-638 and promoted the expression of inflammatory factors and proliferation in HMCs. However, miR-638 mimic significantly decreased the levels of inflammatory factors and inhibited the proliferative ability induced by HG. Conclusions Serum miR-638 expression was low in DN and can be a potentially valuable biomarker for DN. This miRNA seems to influence inflammatory responses and participate in the progression of DN by regulating proliferation.

scholarly journals High Glucose and Lipopolysaccharide Prime NLRP3 Inflammasome via ROS/TXNIP Pathway in Mesangial Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Hong Feng ◽  
Junling Gu ◽  
Fang Gou ◽  
Wei Huang ◽  
Chenlin Gao ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Mesangial Cells ◽  
Central Component ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Interacting Protein

While inflammation is considered a central component in the development in diabetic nephropathy, the mechanism remains unclear. The NLRP3 inflammasome acts as both a sensor and a regulator of the inflammatory response. The NLRP3 inflammasome responds to exogenous and endogenous danger signals, resulting in cleavage of procaspase-1 and activation of cytokines IL-1β, IL-18, and IL-33, ultimately triggering an inflammatory cascade reaction. This study observed the expression of NLRP3 inflammasome signaling stimulated by high glucose, lipopolysaccharide, and reactive oxygen species (ROS) inhibitor N-acetyl-L-cysteine in glomerular mesangial cells, aiming to elucidate the mechanism by which the NLRP3 inflammasome signaling pathway may contribute to diabetic nephropathy. We found that the expression of thioredoxin-interacting protein (TXNIP), NLRP3, and IL-1βwas observed by immunohistochemistry in vivo. Simultaneously, the mRNA and protein levels of TXNIP, NLRP3, procaspase-1, and IL-1βwere significantly induced by high glucose concentration and lipopolysaccharide in a dose-dependent and time-dependent manner in vitro. This induction by both high glucose and lipopolysaccharide was significantly inhibited by N-acetyl-L-cysteine. Our results firstly reveal that high glucose and lipopolysaccharide activate ROS/TXNIP/ NLRP3/IL-1βinflammasome signaling in glomerular mesangial cells, suggesting a mechanism by which inflammation may contribute to the development of diabetic nephropathy.

scholarly journals TAB1 regulates glycolysis and activation of macrophages in diabetic nephropathy

2020 ◽  
Vol 69 (12) ◽  
pp. 1215-1234
Author(s):  
Hanxu Zeng ◽  
Xiangming Qi ◽  
Xingxin Xu ◽  
Yonggui Wu
Keyword(s):  
Diabetic Nephropathy ◽  
Transforming Growth Factor ◽  
Lentiviral Vector ◽  
Hypoxia Inducible Factor ◽  
Damage Index ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Inflammatory Factors

Abstract Objective and design Macrophages exhibit strong phenotypic plasticity and can mediate renal inflammation by polarizing into an M1 phenotype. They play a pivotal role in diabetic nephropathy (DN). Here, we have investigated the regulatory role of transforming growth factor β-activated kinase 1-binding protein 1 (TAB1) in glycolysis and activation of macrophages during DN. Methods TAB1 was inhibited using siRNA in high glucose (HG)-stimulated bone marrow-derived macrophages (BMMs) and lentiviral vector-mediated TAB1 knockdown was used in streptozotocin (STZ)-induced diabetic mice. Western blotting, flow cytometry, qRT-PCR, ELISA, PAS staining and immunohistochemical staining were used for assessment of TAB1/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α), iNOS, glycolysis, inflammation and the clinical and pathological manifestations of diabetic nephropathy. Results We found that TAB1/NF-κB/HIF-1α, iNOS and glycolysis were up-regulated in BMMs under HG conditions, leading to release of further inflammatory factors, Downregulation of TAB1 could inhibit glycolysis/polarization of macrophages and inflammation in vivo and in vitro. Furthermore, albuminuria, the tubulointerstitial damage index and glomerular mesangial expansion index of STZ-induced diabetic nephropathy mice were decreased by TAB1 knockdown. Conclusions Our results suggest that the TAB1/NF-κB/HIF-1α signaling pathway regulates glycolysis and activation of macrophages in DN.

scholarly journals Long Non-Coding RNA NEAT1 Regulates Pyroptosis in Diabetic Nephropathy via Mediating the miR-34c/NLRP3 Axis

2020 ◽  
Vol 45 (4) ◽  
pp. 589-602 ◽  
Author(s):  
Jin-Feng Zhan ◽  
Hong-Wei Huang ◽  
Chong Huang ◽  
Li-Li Hu ◽  
Wen-Wei Xu
Keyword(s):  
Diabetic Nephropathy ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Mesangial Cells ◽  
Receptor Protein ◽  
Luciferase Reporter ◽  
Glomerular Mesangial Cells ◽  
Non Coding Rna ◽  
Vitro Model

Introduction: Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and is considered to be a sterile inflammatory disease. Increasing evidence suggest that pyroptosis and subsequent inflammatory response play a key role in the pathogenesis of DN. However, the underlying cellular and molecular mechanisms responsible for pyroptosis in DN are largely unknown. Methods: The rat models of DN were successfully established by single 65 mg/kg streptozotocin treatment. Glomerular mesangial cells were exposed to 30 mmol/L high glucose media for 48 h to mimic the DN environment in vitro. Gene and protein expressions were determined by quantitative real-time PCR and Western blot. Cell viability and pyroptosis were measured by MTT assay and flow cytometry analysis, respectively. The relationship between lncRNA NEAT1, miR-34c, and Nod-like receptor protein-3 (NLRP3) was confirmed by luciferase reporter assay. Results: We found that upregulation of NEAT1 was associated with the increase of pyroptosis in DN models. miR-34c, as a target gene of NEAT1, mediated the effect of NEAT1 on pyroptosis in DN by regulating the expression of NLRP3 as well as the expressions of caspase-1 and interleukin-1β. Either miR-34c inhibition or NLRP3 overexpression could reverse the accentuation of pyroptosis and inflammation by sh-NEAT1 transfection in the in vitro model of DN. Conclusions: Our findings suggested NEAT1 and its target gene miR-34c regulated cell pyroptosis via mediating NLRP3 in DN, providing new insights into understanding the molecular mechanisms of pyroptosis in the pathogenesis of DN.

Hyperoside ameliorates glomerulosclerosis in diabetic nephropathy by downregulating miR-21

2016 ◽  
Vol 94 (12) ◽  
pp. 1249-1256 ◽  
Author(s):  
Le Zhang ◽  
Siyi He ◽  
Fan Yang ◽  
Hua Yu ◽  
Wei Xie ◽  
...  
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
Mesangial Cells ◽  
Periodic Acid ◽  
Protective Mechanism ◽  
Therapeutic Effects ◽  
Protein Levels ◽  
Tissue Inhibitors Of Metalloproteinase ◽  
Underlying Mechanisms

The purpose of this study was to investigate the therapeutic effects of hyperoside (Hyp) on glomerulosclerosis in diabetic nephropathy and its underlying mechanisms. Blood glucose, kidney mass, and renal function of mice were measured. Renal morphology was observed using hematoxylin and eosin, periodic acid – Schiff’s, and Masson’s trichrome stain. Fibronectin (FN) and collagen IV (COL IV) in kidney were determined by Western blot and immunohistochemical studies. Matrix metalloproteinases (MMP)-2 and -9 and tissue inhibitors of metalloproteinase (TIMP)-1 in renal tissues were detected on both the mRNA and protein levels. miRNA expression and artificial alterations by miRNA agomir transfection were evaluated to investigate the protective mechanism of Hyp in mesangial cells. Hyp effectively improved renal function and physiologic features of db/db mice. Hyp also ameliorated glomerulosclerosis by suppressing FN, COL IV, and TIMP-1 expressions and promoting MMP-9 and MMP-2 expressions. The change in MMP-9 mRNA expression was inconsistent with that in protein levels in kidney, indicating that there was a post-transcriptional regulation. Further exploration in vitro showed that miR-21 was downregulated by Hyp, increasing expression of its target, MMP-9. These results suggest that Hyp can ameliorate glomerulosclerosis in diabetic nephropathy by downregulating miR-21 to increase expression of its target, MMP-9.

Suppressions of chronic glomerular injuries and TGF-β1 production by HGF in attenuation of murine diabetic nephropathy

2004 ◽  
Vol 286 (1) ◽  
pp. F134-F143 ◽  
Author(s):  
Shinya Mizuno ◽  
Toshikazu Nakamura
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Renal Dysfunction ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Renal Diseases ◽  
Glomerular Mesangial Cells ◽  
Diabetic Mice

Diabetic nephropathy is now the leading cause of end-stage renal diseases, and glomerular sclerotic injury is an initial event that provokes renal dysfunction during processes of diabetes-linked kidney disease. Growing evidence shows that transforming growth factor-β1 (TGF-β1) plays a key role in this process, especially in eliciting hypertrophy and matrix overaccumulation. Thus it is important to find a ligand system to antagonize the TGF-β1-mediated pathogenesis under high-glucose conditions. Herein, we provide evidence that hepatocyte growth factor (HGF) targets mesangial cells, suppresses TGF-β1 production, and minimizes glomerular sclerotic changes, using streptozotocin-induced diabetic mice. In our murine model, glomerular sclerogenesis (such as tuft area expansion and collagen deposition) progressed between 6 and 10 wk after the induction of hyperglycemia, during a natural course of diabetic disease. Glomerular HGF expression levels in the diabetic kidney transiently increased but then declined below a basal level, with manifestation of glomerular sclerogenesis. When anti-HGF IgG was injected into mice for 2 wk (i.e., from weeks 4 to 6 after onset of hyperglycemia), these glomerular changes were significantly aggravated. When recombinant HGF was injected into the mice for 4 wk (i.e., between 6 and 10 wk following streptozotocin treatment), the progression of glomerular hypertrophy and sclerosis was almost completely inhibited, even though glucose levels remained unchanged (>500 mg/dl). Even more important, HGF repressed TGF-β1 production in glomerular mesangial cells even under hyperglycemic conditions both in vitro and in vivo. Consequently, not only albuminuria but also tubulointerstitial fibrogenesis were attenuated by HGF. Overall, HGF therapy inhibited the onset of renal dysfunction in the diabetic mice. On the basis of these findings, we wish to emphasize that HGF plays physiological and therapeutic roles in blocking renal fibrogenesis during a course of diabetic nephropathy.

Proteomic profile of primary isolated rat mesangial cells in high-glucose culture condition and decreased expression of PSMA6 in renal cortex of diabetic ratsThis paper is one of a selection of papers published in this special issue entitled “Second International Symposium on Recent Advances in Basic, Clinical, and Social Medicine” and has undergone the Journal's usual peer review process.

2010 ◽  
Vol 88 (4) ◽  
pp. 635-648 ◽  
Author(s):  
Zhiguo Li ◽  
Haojun Zhang ◽  
Xi Dong ◽  
Frank J. Burczynski ◽  
Patrick Choy ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Gel Electrophoresis ◽  
Renal Cortex ◽  
Mesangial Cells ◽  
Diabetic Rats ◽  
Differentially Expressed ◽  
Differentially Expressed Proteins ◽  
Two Dimensional Gel Electrophoresis ◽  
Isolated Rat

Diabetic nephropathy (DN) is one of the most important complications of diabetic patients and is characterized histologically by an accumulation of extracellular matrix (ECM) protein in the glomerular mesangium. Therefore, mesangial cells likely play an important role in the development of diabetic nephropathy. Here, we employed proteomic techniques to investigate the protein profile of rat mesangial cells under high-glucose culture conditions. Primary isolated rat glomerular mesangial cells were cultured under different concentrations of glucose (5.4 mmol·L–1 for normal control and 30 mmol·L–1 for high glucose) for 0, 8, 16, and 72 h, as well as for 25 days. Cellular total proteins were isolated from these cells and employed for two-dimensional gel electrophoresis (2-DE). Differentially expressed proteins were identified by matrix-assisted laser desorption – ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and some of these proteins were documented in rat models of diabetes by Western blot. Rat mesangial cells were successfully isolated in the laboratory and their proliferation rates were significantly inhibited by high glucose. Two-dimensional gel electrophoresis analyses revealed 28 differentially expressed protein spots between the normal and high-glucose groups. After MALDI-TOF-MS analysis, all 28 protein spots were successfully identified with the peptide mass fingerprint (PMF) method. Representatively, SOD1, PCBP1 and PSMA6 were validated by Western blot analysis following protein extractions from the normal and high-glucose groups. Abundance of these proteins was consistent with that found in 2-DE. Moreover, expression of SOD1, PCBP1, and PSMA6 in renal cortex was further examined in two rat models of diabetes (streptozotocin-induced and spontaneous OLETF diabetic models). Abundance of SOD1 and PCBP1 proteins did not show any significant difference between normal control and diabetic rats. However, abundance of the PSMA6 protein was significantly reduced in the renal cortex of both STZ-induced and spontaneous OLETF diabetic rats. Proteomic analysis identified 28 differentially expressed proteins in primary isolated rat mesangial cells between normal and high glucose treatments. Expression of one identified protein was found to be consistent with expression in the renal cortex of two rat diabetic models. Therefore, identification of protein expression patterns in mesangial cells can be employed to develop a therapeutic target for treatment of diabetic nephropathy.

scholarly journals CircSMAD4 alleviates high glucose-induced inflammation, extracellular matrix deposition and apoptosis in mouse glomerulus mesangial cells by relieving miR-377-3p-mediated BMP7 inhibition

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Rina Wu ◽  
Zheli Niu ◽  
Guangwei Ren ◽  
Lin Ruan ◽  
Lijun Sun
Keyword(s):  
Extracellular Matrix ◽  
High Glucose ◽  
Mesangial Cells ◽  
Circular Rna ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Protein Levels ◽  
Matrix Deposition

Abstract Background Diabetic nephropathy (DN) is a common complication of diabetes mellitus. Accumulating studies suggest that the deregulation of circular RNA (circRNA) is involved in DN pathogenesis. This study aimed to investigate the role of circSMAD4 in DN models. Methods Mice were treated with streptozotocin to establish DN models in vivo. Mouse glomerulus mesangial cells (SV40-MES13) were treated with high glucose to establish DN models in vitro. The expression of circSMAD4, miR-377-3p and bone morphogenetic protein 7 (BMP7) mRNA was measured by quantitative real-time PCR (qPCR). The releases of inflammatory factors were examined by ELISA. The protein levels of fibrosis-related markers, apoptosis-related markers and BMP7 were checked by western blot. Cell apoptosis was monitored by flow cytometry assay. The predicted relationship between miR-377-3p and circSMAD4 or BMP7 was validated by dual-luciferase reporter assay or pull-down assay. Results CircSMAD4 was poorly expressed in DN mice and HG-treated SV40-MES13 cells. HG induced SV40-MES13 cell inflammation, extracellular matrix (ECM) deposition and apoptosis. CircSMAD4 overexpression alleviated, while circSMAD4 knockdown aggravated HG-induced SV40-MES13 cell injuries. MiR-377-3p was targeted by circSMAD4, and miR-377-3p enrichment partly reversed the effects of circSMAD4 overexpression. BMP7 was a target of miR-377-3p, and circSMAD4 regulated BMP7 expression by targeting miR-377-3p. MiR-377-3p overexpression aggravated HG-induced injuries by suppressing BMP7. Conclusion CircSMAD4 alleviates HG-induced SV40-MES13 cell inflammation, ECM deposition and apoptosis by relieving miR-377-3p-mediated inhibition on BMP7 in DN progression.

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.

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