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 Dapagliflozin Alleviates Renal Fibrosis by Inhibiting RIP1-RIP3-MLKL-Mediated Necroinflammation in Unilateral Ureteral Obstruction

2022 ◽  
Vol 12 ◽  
Author(s):  
Mei Ying Xuan ◽  
Shang Guo Piao ◽  
Jun Ding ◽  
Qi Yan Nan ◽  
Mei Hua Piao ◽  
...  
Keyword(s):  
Cell Death ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Apoptotic Cell ◽  
Subsequent Development ◽  
Unilateral Ureteral Obstruction ◽  
Apoptotic Cell Death ◽  
Inflammasome Activation ◽  
Renal Tubular

Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, offers renoprotection in diabetes. However, potential for use in nondiabetic kidney disease remains unknown. Herein, we assessed whether dapagliflozin alleviates renal fibrosis by interfering with necroinflammation in a rat model of unilateral ureteral obstruction (UUO) and in vitro. After induction of UUO, rats were administered dapagliflozin daily for seven consecutive days. UUO induced significant renal tubular necrosis and overexpression of RIP1-RIP3-MLKL axis proteins; these coincided with NLRP3 inflammasome activation, and subsequent development of renal fibrosis. Oxidative stress caused by UUO is tightly associated with endoplasmic reticulum stress and mitochondrial dysfunction, leading to apoptotic cell death through Wnt3α/β-catenin/GSK-3β signaling; all of which were abolished by both dapagliflozin and specific RIP inhibitors (necrostatin-1 and GSK872). In H2O2-treated HK-2 cells, dapagliflozin and RIP inhibitors suppressed overexpression of RIP1-RIP3-MLKL proteins and pyroptosis-related cytokines, decreased intracellular reactive oxygen species production and apoptotic cell death, whereas cell viability was improved. Moreover, activated Wnt3α/β-catenin/GSK-3β signaling was inhibited by dapagliflozin and Wnt/β-catenin inhibitor ICG-001. Our findings suggest that dapagliflozin ameliorates renal fibrosis by inhibiting RIP1-RIP3-MLKL-mediated necroinflammation via Wnt3α/β-catenin/GSK-3β signaling in UUO.

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 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 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).

scholarly journals Endogenous Relaxin Is a Naturally Occurring Modulator of Experimental Renal Tubulointerstitial Fibrosis

Endocrinology ◽  
2007 ◽  
Vol 148 (2) ◽  
pp. 660-669 ◽  
Author(s):  
Tim D. Hewitson ◽  
Ishanee Mookerjee ◽  
Rosemary Masterson ◽  
Chongxin Zhao ◽  
Geoffrey W. Tregear ◽  
...  
Keyword(s):  
Gene Knockout ◽  
Smooth Muscle Actin ◽  
Gelatin Zymography ◽  
Progressive Increase ◽  
Tubulointerstitial Fibrosis ◽  
Matrix Metalloproteinase 2 ◽  
Monocyte Chemoattractant Protein 1 ◽  
Naturally Occurring ◽  
Total Collagen ◽  
Renal Tubulointerstitial Fibrosis

Relaxin is a naturally occurring regulator of collagen turnover. In this study, we determined the role of endogenous relaxin in the pathogenesis of primary tubulointerstitial fibrosis after unilateral ureteric obstruction (UUO). Four- to 6-wk-old relaxin (RLX) gene-knockout (RLX−/−) and age-matched wild-type (RLX+/+) mice, with equivalent baseline collagen levels, were subjected to UUO. Obstructed and contralateral kidneys were collected at d 0, 3, and 10 after surgery and analyzed for changes in inflammatory and fibrosis-related markers. UUO was associated with a progressive increase in fibrosis in all obstructed, but not contralateral kidneys. The increase in total collagen (hydroxyproline analysis) was associated with more α-smooth muscle actin (α-SMA) staining (myofibroblasts) and interstitial collagen sub-types (SDS-PAGE; types I, III, and V), whereas gelatin zymography demonstrated increased expression of matrix metalloproteinase-2 after surgery. By d 10 after UUO, there was a 5-fold decrease in RLX mRNA expression (quantitative RT-PCR) in RLX+/+ animals. Total collagen and α-SMA expression were significantly greater in the obstructed kidneys of RLX−/− mice 3 d after UUO (both P < 0.05 vs. RLX+/+ D3 after UUO), but comparable to that in RLX+/+ animals 10 d after UUO. Administration of recombinant H2 relaxin to RLX−/− mice 4 d before UUO ameliorated the increase in collagen and α-SMA expression (both P < 0.05 vs. untreated RLX−/− mice) by d 3 after UUO. Expression of monocyte chemoattractant protein-1 and macrophage infiltration (inflammation) in addition to that of matrix metalloproteinases was unaffected by genotype after UUO. These combined data demonstrate that endogenous RLX acts as a modulating factor in tubulointerstitial fibrosis, a hallmark of progressive renal disease. This is likely to be via direct effects on renal myofibroblast function.

TNF-α mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling

2005 ◽  
Vol 288 (2) ◽  
pp. F406-F411 ◽  
Author(s):  
R. Misseri ◽  
D. R. Meldrum ◽  
C. A. Dinarello ◽  
P. Dagher ◽  
K. L. Hile ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Apoptosis ◽  
Renal Cell ◽  
Fas Ligand ◽  
Tubular Cell ◽  
Caspase 8 ◽  
Renal Tubular Cell ◽  
Rt Pcr ◽  
Tnf Α ◽  
Renal Tubular

Obstruction of the upper urinary tract induces a progressive loss in renal mass through apoptotic renal cell death. Although TNF-α has been implicated in ischemia-reperfusion-induced apoptotic renal cell death, its role in obstructive renal cell apoptosis remains unknown. To study this, male Sprague-Dawley rats were subjected to left unilateral ureteral obstruction vs. sham operation. Twenty-four hours before surgery and every 84 h thereafter, rats received either vehicle or a pegylated form of soluble TNF receptor type 1 (PEG-sTNFR1). The kidneys were harvested 1, 3, or 7 days postoperatively, and tissue samples were subsequently analyzed for TNF-α (ELISA, RT-PCR), Fas ligand (RT-PCR), apoptosis (TUNEL, ELISA), and caspase 8 and 3 activity (Western blot). Renal obstruction induced increased tissue TNF-α and Fas ligand mRNA levels, TNF-α protein production, apoptotic renal tubular cell death, and elevated caspase 8 and 3 activity, whereas treatment with PEG-sTNFR1 significantly reduced obstruction-induced TNF-α production, renal tubular cell apoptosis, and caspase activity. PEG-sTNFR1 did not significantly alter Fas ligand expression. These results demonstrate that TNF-α mediates obstruction-induced renal tubular cell apoptosis and proapoptotic signaling and identify TNF-α neutralization as a potential therapeutic option for the amelioration of obstruction-induced renal injury.

Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction

2008 ◽  
Vol 294 (3) ◽  
pp. F508-F517 ◽  
Author(s):  
Lin Wang ◽  
Ji-Yang Sophie Lee ◽  
Joon Hyeok Kwak ◽  
Yanjuan He ◽  
Sung Il Kim ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Low Dose ◽  
Tissue Injury ◽  
Unilateral Ureteral Obstruction ◽  
Tubulointerstitial Fibrosis ◽  
In Vivo Model ◽  
Obstructive Nephropathy ◽  
Protective Effects

Tubulointerstitial fibrosis is a hallmark of chronic progressive kidney disease leading to end-stage renal failure. An endogenous product of heme oxygenase activity, carbon monoxide (CO), has been shown to exert cytoprotection against tissue injury. Here, we explored the effects of exogenous administration of low-dose CO in an in vivo model of renal fibrosis induced by unilateral ureteral obstruction (UUO) and examined whether CO can protect against kidney injury. UUO in mice leads to increased extracellular matrix (ECM) deposition and tubulointerstitial fibrosis within 4 to 7 days. Kidneys of mice exposed to low-dose CO, however, had markedly reduced ECM deposition after UUO. Moreover, low-dose CO treatment inhibited the induction of α-smooth muscle actin (α-SMA) and major ECM proteins, type 1 collagen and fibronectin, in kidneys after UUO. In contrast, these anti-fibrotic effects of CO treatment were abrogated in mice carrying null mutation of Mkk3, suggesting involvement of the MKK3 signaling pathway in mediating the CO effects. Additionally, in vitro CO exposure markedly inhibited TGF-β1-induced expression of α-SMA, collagen, and fibronectin in renal proximal tubular epithelial cells. Our findings suggest that low-dose CO exerts protective effects, via the MKK3 pathway, to inhibit development of renal fibrosis in obstructive nephropathy.

Extracellular nucleotides from dying cells act as molecular signals to promote wound repair in renal tubular injury

2014 ◽  
Vol 307 (12) ◽  
pp. F1404-F1411 ◽  
Author(s):  
Shunsaku Nakagawa ◽  
Tomohiro Omura ◽  
Atsushi Yonezawa ◽  
Ikuko Yano ◽  
Takayuki Nakagawa ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Epithelial Cells ◽  
Wound Repair ◽  
Purinergic Signaling ◽  
Rat Kidney ◽  
Extracellular Nucleotides ◽  
Tubular Damage ◽  
Danger Signals ◽  
Renal Tubular

Acute kidney injury (AKI) often correlates with poor prognosis and is followed by various severe unfavorable systemic outcomes. It is important to understand the pathophysiology of AKI for the development of novel therapeutic approaches toward promoting renal regeneration after injury. Recent studies have indicated that AKI-induced tubular cell death plays an active role in the onset of tissue regeneration; however, the mechanisms underlying renal tubular repair after injury have yet to be understood. In the present study, we explored molecules that might serve as “danger” signals in mediating tubular regeneration. Kidneys of rats systemically administered the nephrotoxicant cisplatin (to induce AKI) exhibited massive cell proliferation. The proportion of proliferating cells in the total cell distribution was highest in the outer stripe of the outer medulla coincided with where the tubular damage was the most severe in this study. This finding suggests that soluble factors may have been released from damaged cells to stimulate the proliferation of neighboring tubular epithelial cells. In elucidating the mechanism of dying cell-to-surviving cell communication using normal rat kidney NRK-52E epithelial cells, we found a significant increase in ATP levels in supernatants of these cells after the induction of cell death using ultraviolet irradiation. Furthermore, treatment of conditioned supernatants with apyrase or suramin, which inhibits purinergic signaling, resulted in significant decreases in cell proliferation and migration activities. These results demonstrate a novel role for extracellular nucleotides, probably as danger signals in aggravating tubular regeneration after AKI.

scholarly journals Hydroxychloroquine Inhibits Macrophage Activation and Attenuates Renal Fibrosis After Ischemia-Reperfusion Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Haofeng Zheng ◽  
Yannan Zhang ◽  
Jiannan He ◽  
Zhe Yang ◽  
Rui Zhang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Renal Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Tubulointerstitial Fibrosis ◽  
Health Concern ◽  
Dependent Manner ◽  
Renal Tubulointerstitial Fibrosis

Chronic kidney disease (CKD), which is associated with high morbidity, remains a worldwide health concern, while effective therapies remain limited. Hydroxychloroquine (HCQ), which mainly targets toll-like receptor-7 (TLR-7) and TLR-9, is associated with a lower risk of incident CKD. Taking into account that TLR-9 is involved in the development of renal fibrosis and serves as a potential therapy target for CKD, we investigated whether HCQ could attenuate CKD via TLR-9 signal pathway. The effects of HCQ on renal tubulointerstitial fibrosis were further explored using a mouse model of renal tubulointerstitial fibrosis after ischemia/reperfusion injury. Bone marrow-derived macrophages were isolated to explore the effects of HCQ in vitro. Judicious use of HCQ efficiently inhibited the activation of macrophages and MAPK signaling pathways, thereby attenuating renal fibrosis in vivo. In an in vitro model, results showed that HCQ promoted apoptosis of macrophages and inhibited activation of macrophages, especially M2 macrophages, in a dose-dependent manner. Because TLR-7 is not involved in the development of CKD post-injury, a TLR-9 knockout mouse was used to explore the mechanisms of HCQ. The effects of HCQ on renal fibrosis and macrophages decreased after depletion of TLR-9 in vivo and in vitro. Taken together, this study indicated that proper use of HCQ could be a new strategy for anti-fibrotic therapy and that TLR-9 could be a potential therapeutic target for CKD following acute kidney injury.

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