scholarly journals PP2 Ameliorates Renal Fibrosis by Regulating the NF-κB/COX-2 and PPARγ/UCP2 Pathway in Diabetic Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-24
Author(s):  
Jinying Wei ◽  
Xinna Deng ◽  
Yang Li ◽  
Runmei Li ◽  
Zhaohua Yang ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Mesangial Cells ◽  
Tubulointerstitial Fibrosis ◽  
Glomerular Mesangial Cells ◽  
Diabetic Mice ◽  
Ucp2 Expression ◽  
Renal Tubulointerstitial Fibrosis ◽  
Proximal Tubular ◽  
Cox 2 ◽  
Geo Database

Renal fibrosis is characterized by glomerulosclerosis and tubulointerstitial fibrosis in diabetic nephropathy (DN). We aimed to evaluate the effects of PP2 on renal fibrosis of DN. GSE33744 and GSE86300 were downloaded from the GEO database. Firstly, 839 DEGs were identified between nondiabetic and diabetic mice renal glomerular samples. COX-2 was selected to assess the effects of PP2 on renal glomerulosclerosis. In db/db mice, PP2 decreased the expression of COX-2, phosphorylated p65, and fibrotic proteins, accompanied with attenuated renal glomerulosclerosis. In cultured glomerular mesangial cells, high glucose- (HG-) induced p65 phosphorylation and COX-2 expression were attenuated by PP2 or NF-κB inhibitor PDTC. PP2, PDTC, or COX-2 inhibitor NS-398 ameliorated abnormal proliferation and expression of fibrotic proteins induced by HG. Secondly, 238 DEGs were identified between nondiabetic and diabetic mice renal cortex samples. UCP2 was selected to assess the effects of PP2 on renal tubulointerstitial fibrosis. In db/db mice, PP2 decreased the expression of PPARγ and UCP2, accompanied with attenuated renal tubulointerstitial fibrosis and EMT. In cultured proximal tubular cells, HG-induced PPARγ and UCP2 expression was inhibited by PP2 or PPARγ antagonist GW9662. PP2, GW9662, or UCP2 shRNA ameliorated HG-induced EMT. These results indicated that PP2 ameliorated renal fibrosis in diabetic mice.

scholarly journals Inhibition of ROCK2 alleviates renal fibrosis and the metabolic disorders in the proximal tubular epithelial cells

2020 ◽  
Vol 134 (12) ◽  
pp. 1357-1376 ◽  
Author(s):  
Ran You ◽  
Wei Zhou ◽  
Yanwei Li ◽  
Yue Zhang ◽  
Songming Huang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Renal Fibrosis ◽  
Tubulointerstitial Fibrosis ◽  
Related Factor ◽  
Tubular Epithelial Cells ◽  
Renal Tubulointerstitial Fibrosis ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Tgf Β1

Abstract Non-specific inhibition of Rho-associated kinases (ROCKs) alleviated renal fibrosis in the unilateral ureteral obstruction (UUO) model, while genetic deletion of ROCK1 did not affect renal pathology in mice. Thus, whether ROCK2 plays a role in renal tubulointerstitial fibrosis needs to be clarified. In the present study, a selective inhibitor against ROCK2 or genetic approach was used to investigate the role of ROCK2 in renal tubulointerstitial fibrosis. In the fibrotic kidneys of chronic kidney diseases (CKDs) patients, we observed an enhanced expression of ROCK2 with a positive correlation with interstitial fibrosis. In mice, the ROCK2 protein level was time-dependently increased in the UUO model. By treating CKD animals with KD025 at the dosage of 50 mg/kg/day via intraperitoneal injection, the renal fibrosis shown by Masson’s trichrome staining was significantly alleviated along with the reduced expression of fibrotic genes. In vitro, inhibiting ROCK2 by KD025 or ROCK2 knockdown/knockout significantly blunted the pro-fibrotic response in transforming growth factor-β1 (TGF-β1)-stimulated mouse renal proximal tubular epithelial cells (mPTCs). Moreover, impaired cellular metabolism was reported as a crucial pathogenic factor in CKD. By metabolomics analysis, we found that KD025 restored the metabolic disturbance, including the impaired glutathione metabolism in TGF-β1-stimulated tubular epithelial cells. Consistently, KD025 increased antioxidative stress enzymes and nuclear erythroid 2-related factor 2 (Nrf2) in fibrotic models. In addition, KD025 decreased the infiltration of macrophages and inflammatory response in fibrotic kidneys and blunted the activation of macrophages in vitro. In conclusion, inhibition of ROCK2 may serve as a potential novel therapy for renal tubulointerstitial fibrosis in CKD.

scholarly journals DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiaozhou Li ◽  
Jian Pan ◽  
Huiling Li ◽  
Guangdi Li ◽  
Xiangfeng Liu ◽  
...  
Keyword(s):  
Low Dose ◽  
Aristolochic Acid ◽  
Tissue Growth ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Renal Tubulointerstitial Fibrosis ◽  
Proximal Tubular ◽  
Apoptosis And Inflammation

Abstract Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN). However, the role and regulation of proximal tubular DsbA-L for renal tubulointerstitial fibrosis (TIF) remains unclear. In current study, we found that a proximal tubules-specific DsbA-L knockout mouse (PT-DsbA-L-KO) attenuated UUO-induced TIF, renal cell apoptosis and inflammation. Mechanistically, the DsbA-L interacted with Hsp90 in mitochondria of BUMPT cells which activated the signaling of Smad3 and p53 to produce connective tissue growth factor (CTGF) and then resulted in accumulation of ECM of BUMPT cells and mouse kidney fibroblasts. In addition, the progression of TIF caused by UUO, ischemic/reperfusion (I/R), aristolochic acid, and repeated acute low-dose cisplatin was also alleviated in PT-DsbA-L-KO mice via the activation of Hsp90 /Smad3 and p53/CTGF axis. Finally, the above molecular changes were verified in the kidney biopsies from patients with obstructive nephropathy (Ob). Together, these results suggest that DsbA-L in proximal tubular cells promotes TIF via activation of the Hsp90 /Smad3 and p53/CTGF axis.

scholarly journals Interaction between V-ATPase B2 and (Pro) renin Receptors in Promoting the progression of Renal Tubulointerstitial Fibrosis

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Yun Liu ◽  
Sujun Zuo ◽  
Xiaoyan Li ◽  
Jinjin Fan ◽  
Xueqin Cao ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Smooth Muscle Actin ◽  
Tubulointerstitial Fibrosis ◽  
Dependent Manner ◽  
Tubular Epithelial Cells ◽  
Atpase Inhibitor ◽  
Renal Tubulointerstitial Fibrosis ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Atpase Subunits

Abstract To investigate the levels of (Pro) renin receptor [(P) RR], α-smooth muscle actin (α-SMA), fibronectin (FN), and vacuolar H+-ATPase (V-ATPase) subunits (B2, E, and c) in rat unilateral ureteral obstruction (UUO) models and rat proximal tubular epithelial cells (NRK-52E) treated with prorenin to elucidate the role of V-ATPase in these processes by activating the (P) RR. UUO significantly upregulated (P) RR, V-ATPase subunits, α-SMA and FN expression in tubulointerstitium or tubular epithelial cells. A marked colocalization of (P) RR and the B2 subunit was also observed. Prorenin treatment upregulated α-SMA, FN, (P) RR, and V-ATPase subunits and activity in NRK52E cell in a dose- and time-dependent manner. The V-ATPase inhibitor bafilomycin A1 partially blocked prorenin-induced (P) RR, FN, and α-SMA expression. Co-immunoprecipitate and immunofluorescence results demonstrated that the V-ATPase B2 subunit bound to the (P) RR, which was upregulated after prorenin stimulation. Either siRNA-mediated (P) RR or B2 subunit knockdown partially reduced V-ATPase activity and attenuated prorenin-induced FN and α-SMA expression. From the data we can assume that activation of (P) RR and V-ATPase may play an important role in tubulointerstitial fibrosis with possible involvement of interaction of V-ATPase B2 subunit and (P)RR.

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.

scholarly journals Identification of Tisp40 as an Essential Regulator of Renal Tubulointerstitial Fibrosis via TGF-β/Smads Pathway

2017 ◽  
Vol 42 (2) ◽  
pp. 697-712 ◽  
Author(s):  
Cheng-cheng Xiao ◽  
Jie Zhang ◽  
Peng-cheng Luo ◽  
Cong Qin ◽  
Yang Du ◽  
...  
Keyword(s):  
Western Blot ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Tubulointerstitial Fibrosis ◽  
Mesenchymal Transition ◽  
Renal Tubulointerstitial Fibrosis

Background: Tisp40, a transcription factor of the CREB/CREM family, is involved in cell proliferation, differentiation and other biological functions, but its role in renal tubulointerstitial fibrosis is unknown. Methods: In our study, we investigated the effects of Tisp40 on extracellular matrix (ECM) accumulation, epithelial-mesenchymal transition (EMT) and the underlying molecular mechanisms in transforming growth factor-β (TGF-β)-stimulated TCMK-1 cells by quantitative real-time polymerase chain reaction (qPCR), Western blot analysis and immunofluorescence in vitro, and further explored the role of Tisp40 on renal fibrosis induced by ischemia-reperfusion (I/R) by qPCR, Western blot analysis, hydroxyproline analysis, Masson trichrome staining and immunohistochemistry staining in vivo. Results: The data showed that Tisp40 was upregulated in a model of renal fibrosis induced by I/R injury (IRI). Upon IRI, Tisp40-deficient mice showed attenuated renal fibrosis compared with wild-type mice. Furthermore, the expression of α-smooth muscle actin, E-cadherin, fibronectin, and collagen I was suppressed. Tisp40 overexpression aggravated ECM accumulation and EMT in the TGF-β-stimulated TCMK-1 cell line, whereas the opposite occurred in cells treated with small interfering RNA (siRNA) targeting Tisp40. Importantly, it is changes in the Smad pathway that attenuate renal fibrosis. Conclusion: These findings suggest that Tisp40 plays a critical role in the TGF-β/ Smads pathway involved in this process. Hence, Tisp40 could be a useful therapeutic target in the fight against renal tubulointerstitial fibrosis.

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.

IGF-I and insulin amplify IL-1β-induced nitric oxide and prostaglandin biosynthesis

1998 ◽  
Vol 274 (4) ◽  
pp. F673-F679 ◽  
Author(s):  
Zhonghong Guan ◽  
Shaavhree Y. Buckman ◽  
Lisa D. Baier ◽  
Aubrey R. Morrison
Keyword(s):  
Nitric Oxide ◽  
Mesangial Cells ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
No Production ◽  
Glomerular Mesangial Cells ◽  
Igf I ◽  
Mitogen Activated Protein ◽  
Transduction Mechanisms ◽  
Cox 2

The inflammatory cytokine interleukin-1β (IL-1β) induces both cyclooxygenase-2 (Cox-2) and the inducible nitric oxide synthase (iNOS) with concomitant release of PGs and nitric oxide (NO) by glomerular mesangial cells. In our current studies, we determine whether insulin and IGF-I are involved in the signal transduction mechanisms resulting in IL-1β-induced NO and PGE2biosynthesis in renal mesangial cells. We demonstrate that both insulin and IGF-I increase IL-1β-induced Cox-2 and iNOS protein expression, which in turn enhance PGE2 and NO production. Our data also indicate that both insulin and IGF-I enhance IL-1β-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation and SAPK activation. These findings implicate the possible role of the MAPK pathway in mediating the effects of insulin and IGF-I on the upregulation of cytokine-stimulated NO and PG biosynthesis. Together, our results indicate that IGF-I and insulin may function to modulate the renal inflammatory process.

The growth hormone-insulin-like growth factor axis in kidney

1989 ◽  
Vol 257 (4) ◽  
pp. F503-F514 ◽  
Author(s):  
M. R. Hammerman
Keyword(s):  
Growth Hormone ◽  
Growth Factors ◽  
Growth Factor ◽  
Proximal Tubule ◽  
Mesangial Cells ◽  
Transport Processes ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Igf I ◽  
Proximal Tubular

Growth hormone (GH) exerts a variety of metabolic and anabolic effects on skeletal and soft tissues including kidney. Some of these actions are mediated directly, whereas others result from GH-dependent synthesis and release of polypeptide growth factors designated insulin-like growth factors (IGFs). Receptors for GH are present in proximal tubule and GH directly stimulates gluconeogenesis at this site. IGF receptors are found in glomerulus and proximal tubule. Mechanisms for signal transduction by GH and IGFs have been characterized using proximal tubular basolateral membranes. IGFs regulate metabolic and transport processes in cultured glomerular mesangial cells and in isolated proximal tubular cells. IGF I is synthesized in cultured mesangial cells and is produced in a GH-dependent manner in cortical and medullary collecting duct. Evidence has accumulated that IGF I of renal origin functions as a paracrine growth factor in the settings of GH-induced hypertrophy and compensatory hypertrophy of the kidney, and in the setting of proximal tubular regeneration following ischemic injury. IGFs are embryonal mitogens and IGF II may act as a transforming agent for Wilms' tumor. Further characterization of the GH-IGF axis in kidney will provide additional insights into the roles of these peptides as regulators of renal function, growth, and development.

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