Pathogenesis and management of renal fibrosis induced by unilateral ureteral obstruction.

Regardless of the underlying etiology, renal fibrosis is the final histological outcome of progressive kidney disease. Unilateral ureteral obstruction (UUO) is an ideal and reproducible experimental rodent model of renal fibrosis, which is characterized by tubulointerstitial inflammatory responses, accumulation of extracellular matrix, tubular dilatation and atrophy, and fibrosis. The magnitude of UUO-induced renal fibrosis is experimentally manipulated by the species chosen, animal age, and the severity and duration of the obstruction, while relief of the obstruction allows the animal to recover from fibrosis. The pathogenesis of renal fibrosis is complex and multifactorial and is orchestrated by activation of renin-angiotensin system (RAS), oxidative stress, inflammatory response, transforming growth factor beta 1-Smad pathway, activated myofibroblasts, cell death (apoptosis, autophagy, ferroptosis, and necroptosis), destruction of intracellular organelles, and signaling pathway. The current therapeutic approaches have limited efficacy. Inhibition of RAS and use of antioxidants and antidiabetic drugs, such as inhibitors of sodium-glucose cotransporter 2 and dipeptidyl peptidase-4, have recently gained attention as therapeutic strategies to prevent renal scarring. This literature review highlights the state of the art regarding the molecular mechanisms relevant to the management of renal fibrosis caused by UUO.

The angiotensin receptor neprilysin inhibitor LCZ696 attenuates renal fibrosis via ASK1/JNK/p38 MAPK-mediated apoptosis in unilateral ureteral obstruction.

The angiotensin receptor neprilysin inhibitor LCZ696 affords superior cardioprotection and renoprotection compared with renin-angiotensin blockade monotherapy, but the underlying mechanisms remain elusive. Herein, we evaluated whether LCZ696 attenuates renal fibrosis by inhibiting ASK1/JNK/p38 mitogen-activated protein kinase (MAPK)-mediated apoptosis in a rat model of unilateral ureteral obstruction (UUO) and in vitro. Rats with UUO were treated daily for 7 days with LCZ696, valsartan, or the selective ATP competitive inhibitor of apoptosis signal-regulating kinase 1 (ASK1), GS-444217. The effects of LCZ696 on renal injury were examined by assessing the histopathology, oxidative stress, intracellular organelles, apoptotic cell death, and MAPK pathways. H2O2-exposed human kidney 2 (HK-2) cells were also examined. LCZ696 and valsartan treatment significantly attenuated renal fibrosis caused by UUO, and this was paralleled by downregulation of proinflammatory cytokines and decreased inflammatory cell influx. Intriguingly, LCZ696 had stronger effects on renal fibrosis and inflammation than valsartan. UUO-induced oxidative stress triggered mitochondrial destruction and endoplasmic reticulum stress, which resulted in apoptotic cell death; these effects were reversed by LCZ696. Both GS-444217 and LCZ696 hampered the expression of death-associated ASK1/JNK/p38 MAPKs. In H2O2-treated HK-2 cells, LCZ696 and GS-444217 increased cell viability but decreased the production of intracellular reactive oxygen species and MitoSOX and apoptotic cell death. Both agents also deactivated H2O2-stimulated activation of ASK1/JNK/p38 MAPKs. These findings suggest that LCZ696 protects against UUO-induced renal fibrosis by inhibiting ASK1/JNK/p38 MAPK-mediated apoptosis.

Coenzyme Q10 attenuates renal fibrosis by inhibiting RIP1-RIP3-MLKL-mediated necroinflammation via Wnt3α/ß-catenin/GSK-3ß signaling in unilateral ureteral obstruction.

OBJECTIVE: Coenzyme Q10 (CoQ10) protects against various types of injury, but its role in preventing renal scarring in chronic kidney disease remains an open question. Herein, we evaluated whether CoQ10 attenuates renal fibrosis by interfering with necroinflammation in a rat model of unilateral ureteral obstruction (UUO) and in vitro. METHODS: Rats with UUO were treated daily with CoQ10 or an RIP inhibitor (necrostatin-1 or GSK872) for 7 days. The influence of CoQ10 on renal injury caused by UUO was evaluated by histopathology and analysis of gene expression, oxidative stress, intracellular organelles, apoptosis, and Wnt3α/ß-catenin/GSK-3ß signaling·H2O2-exposed human kidney (HK-2) cells were also examined after treatment with CoQ10 or an RIP inhibitor. RESULTS: UUO induced marked renal tubular necrosis, upregulation of RIP1-RIP3-MLKL axis proteins, activation of the NLRP3 inflammasome, and evolution of renal fibrosis. UUO-induced oxidative stress evoked excessive endoplasmic reticulum stress and mitochondrial dysfunction, which triggered apoptotic cell death through Wnt3α/ß-catenin/GSK-3ß signaling. All of these effects were mitigated by CoQ10 or an RIP inhibitor. In H2O2-treated HK-2 cells, CoQ10 or an RIP inhibitor suppressed the expression of RIP1-RIP3-MLKL proteins and pyroptosis-related cytokines, and hindered the production of intracellular reactive oxygen species as shown by MitoSOX Red staining and apoptotic cell death but increased cell viability. The CoQ10 or Wnt/ß-catenin inhibitor ICG-001 deactivated H2O2-stimulated activation of Wnt3α/ß-catenin/GSK-3ß signaling. CONCLUSION: These findings suggest that CoQ10 attenuates renal fibrosis by inhibiting RIP1-RIP3-MLKL-mediated necroinflammation via Wnt3α/ß-catenin/GSK-3ß signaling in UUO.

Inhibition of RIP1-RIP3-mediated necroptosis attenuates renal fibrosis via Wnt3α/ß-catenin/GSK-3ß signaling in unilateral ureteral obstruction.

Renal fibrosis represents the final common outcome of chronic kidney disease of virtually any etiology. However, the mechanism underlying the evolution of renal fibrosis remains to be addressed. This study sought to clarify whether RIP1-RIP3-mediated necroptosis is involved in renal fibrosis via Wnt3α/ß-catenin/GSK-3ß signaling in vitro and in a rat model of unilateral ureteral obstruction (UUO). Rats with UUO were administered RIP inhibitors (necrostatin-1 or GSK872) or ß-catenin/TCF inhibitor ICG-001 daily for 7 consecutive days. UUO caused significant renal tubular necrosis and overexpression of RIP1-RIP3-MLKL axis proteins, and was accompanied by activation of the NLRP3 inflammasome and renal fibrosis. Oxidative stress caused by UUO was closely associated with endoplasmic reticulum stress and mitochondrial dysfunction, which resulted in apoptotic cell death via Wnt3α/ß-catenin/GSK-3ß signaling. All of these effects were abolished by an RIP inhibitor (necrostatin-1 or GSK872) or ICG-001. In H2O2-treated HK-2 cells, both RIP inhibitor and ICG-001 decreased intracellular reactive oxygen species production and apoptotic cells, but increased cell viability. Activated Wnt3α/ß-catenin/GSK-3ß signaling was decreased by either RIP inhibitor or ICG-001. Our findings suggest that RIP1-RIP3-mediated necroptosis contributes to the development of renal fibrosis via Wnt3α/ß-catenin/GSK-3ß signaling in UUO and may be a therapeutic target for protection against renal scarring of other origins.

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

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/ß-catenin/GSK-3ß 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/ß-catenin/GSK-3ß signaling was inhibited by dapagliflozin and Wnt/ß-catenin inhibitor ICG-001. Our findings suggest that dapagliflozin ameliorates renal fibrosis by inhibiting RIP1-RIP3-MLKL-mediated necroinflammation via Wnt3α/ß-catenin/GSK-3ß signaling in UUO.

Nicotine exacerbates tacrolimus-induced renal injury by programmed cell death.

BACKGROUND/AIMS: Cigarette smoking is an important modifiable risk factor in kidney disease progression. However, the underlying mechanisms for this are lacking. This study aimed to assess whether nicotine (NIC), a major toxic component of cigarette smoking, would exacerbates tacrolimus (TAC)-induced renal injury. METHODS: Sprague-Dawley rats were treated daily with NIC, TAC, or both drugs for 4 weeks. The influence of NIC on TAC-caused renal injury was examined via renal function, histopathology, oxidative stress, mitochondria, endoplasmic reticulum (ER) stress, and programmed cell death (apoptosis and autophagy). RESULTS: Both NIC and TAC significantly impaired renal function and histopathology, while combined NIC and TAC treatment aggravated these parameters beyond the effects of either alone. Increased oxidative stress, ER stress, mitochondrial dysfunction, proinf lammatory and profibrotic cytokine expressions, and programmed cell death from either NIC or TAC were also aggravated by the two combined. CONCLUSION: Our observations suggest that NIC exacerbates chronic TAC nephrotoxicity, implying that smoking cessation may be beneficial for transplant smokers taking TAC.