Dataset Information

Anlotinib Alleviates Renal Fibrosis via Inhibition of the ERK and AKT Signaling Pathways.

ABSTRACT:

Purpose

We examined whether anlotinib can attenuate folic acid-induced and unilateral ureteral obstruction-induced renal fibrosis and explored the underlying antifibrotic mechanism.

Materials and methods

We have evaluated the effects of anlotinib on folic acid-induced and unilateral ureteral obstruction-induced renal fibrosis in mice through in vivo experiments of unilateral ureteral obstruction or folic acid-induced interstitial fibrosis and in vitro models of transforming growth factor-β1 induced HK-2 human renal proximal tubule cells. Serum renal function parameters and inflammatory cytokine levels were measured, and histological changes of renal injury and fibrosis were analyzed by HE staining and immunohistochemistry. Immunohistochemistry and Western blotting were used to determine the mechanism of action of anlotinib in ameliorating renal fibrosis.

Results

Anlotinib improved proteinuria and reduced renal impairment in folic acid-induced mouse models of renal fibrosis. Anlotinib reduced tubular injury, deposition of tubular extracellular matrix, and expression of alpha-smooth muscle actin, transforming growth factor-β1, and cytosolic inflammatory factors compared with controls.

Conclusions

Anlotinib ameliorated renal function, improved extracellular matrix deposition, reduced protein levels of epithelial-mesenchymal transition markers, and decreased cellular inflammatory factors. Anlotinib reduced renal injury and fibrosis by inhibiting the transforming growth factor-β1 signaling pathway through AKT and ERK channels.

SUBMITTER: Sun D

PROVIDER: S-EPMC9966823 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Anlotinib Alleviates Renal Fibrosis via Inhibition of the ERK and AKT Signaling Pathways.

Sun Donglin D Guo Jing J Liang Weifei W Chen Yangxiao Y Chen Xiangqiu X Wang Li L

Oxidative medicine and cellular longevity 20230218

<h4>Purpose</h4>We examined whether anlotinib can attenuate folic acid-induced and unilateral ureteral obstruction-induced renal fibrosis and explored the underlying antifibrotic mechanism.<h4>Materials and methods</h4>We have evaluated the effects of anlotinib on folic acid-induced and unilateral ureteral obstruction-induced renal fibrosis in mice through in vivo experiments of unilateral ureteral obstruction or folic acid-induced interstitial fibrosis and in vitro models of transforming growth ...[more]

PMID: 36852327

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Project description:IntroductionHigh calorie intake is known to induce nonalcoholic fatty liver disease (NAFLD) by promoting chronic inflammation. However, the mechanisms are poorly understood.ObjectivesThis study examined the roles of ANGPTL8 in the regulation of NAFLD-associated liver fibrosis progression induced by high fat diet (HFD)-mediated inflammation.MethodsThe ANGPTL8 concentration was measured in serum samples from liver cancer and liver cirrhosis patients. ANGPTL8 knockout(KO) mice were used to induce disease models (HFD, HFHC and CCL4) followed by pathological staining, western blot and immunohistochemistry. Hydrodynamic injection of an adeno-associated virus 8 (AAV8) was used to establish a model for restoring ANGPTL8 expression specifically in ANGPTL8 KO mice livers. RNA-sequencing, protein array, Co-IP, etc. were used to study ANGPTL8's mechanisms in regulating liver fibrosis progression, and drug screening was used to identify an effective inhibitor of ANGPTL8 expression.ResultsANGPTL8 level is associated with liver fibrogenesis in both cirrhosis and hepatocellular carcinoma patients. Mouse studies demonstrated that ANGPTL8 deficiency suppresses HFD-stimulated inflammatory activity, hepatic steatosis and liver fibrosis. The AAV-mediated restoration of liver ANGPTL8 expression indicated that liver-derived ANGPTL8 accelerates HFD-induced liver fibrosis. Liver-derived ANGPTL8, as a proinflammatory factor, activates HSCs (hepatic stellate cells) by interacting with the LILRB2 receptor to induce ERK signaling and increase the expression of genes that promote liver fibrosis. The FDA-approved anti-diabetic drug metformin, an ANGPTL8 inhibitor, inhibited HFD-induced liver fibrosis in vivo.ConclusionsOur data support that ANGPTL8 is a proinflammatory factor that accelerates NAFLD-associated liver fibrosis induced by HFD. The serum ANGPTL8 level may be a potential and specific diagnostic marker for liver fibrosis, and targeting ANGPTL8 holds great promise for developing innovative therapies to treat NAFLD-associated liver fibrosis.

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Dataset Information

Anlotinib Alleviates Renal Fibrosis via Inhibition of the ERK and AKT Signaling Pathways.

Purpose

Materials and methods

Results

Conclusions

Publications

Anlotinib Alleviates Renal Fibrosis via Inhibition of the ERK and AKT Signaling Pathways.

Similar Datasets

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