ASK1 inhibitor treatment suppresses p38/JNK signalling with reduced kidney inflammation and fibrosis in rat crescentic glomerulonephritis

Journal of Cellular and Molecular Medicine
Liv A AmosYingjie Han

Abstract

Activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun amino terminal kinase (JNK) is prominent in human crescentic glomerulonephritis. p38 and JNK inhibitors suppress crescentic disease in animal models; however, the upstream mechanisms inducing activation of these kinases in crescentic glomerulonephritis are unknown. We investigated the hypothesis that apoptosis signal-regulating kinase 1 (ASK1/MAP3K5) promote p38/JNK activation and renal injury in models of nephrotoxic serum nephritis (NTN); acute glomerular injury in SD rats, and crescentic disease in WKY rats. Treatment with the selective ASK1 inhibitor, GS-444217 or vehicle began 1 hour before nephrotoxic serum injection and continued until animals were killed on day 1 (SD rats) or 14 (WKY rats). NTN resulted in phosphorylation (activation) of p38 and c-Jun in both models which was substantially reduced by ASK1 inhibitor treatment. In SD rats, GS-444217 prevented proteinuria and glomerular thrombosis with suppression of macrophage activation on day 1 NTN. In WKY rats, GS-444217 reduced crescent formation, prevented renal impairment and reduced proteinuria on day 14 NTN. Macrophage activation, T-cell infiltration and renal fibrosis were also reduced by GS-4442...Continue Reading

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Citations

Feb 28, 2019·Clinical and Experimental Pharmacology & Physiology·Yingjie HanDavid J Nikolic-Paterson
Mar 2, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Zhen HuangYan-Zhou Zhang
Jan 24, 2020·The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology·Greg H TeschDavid J Nikolic-Paterson
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May 27, 2020·Biomolecules & Therapeutics·Young-Chan YoonSoon-Sun Hong
Apr 20, 2021·BioMed Research International·Zhao GuoWen-Yuan Ding
Oct 1, 2021·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jie-Lei ZhangYan-Zhou Zhang

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Methods Mentioned

BETA
Protein Assay
biopsy

Software Mentioned

Gel Pro Analyzer
GraphPad Prism

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