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

被引：61

作者：

Amos, Liv A. ^{[1
,2
]}

Ma, Frank Y. ^{[1
,2
]}

Tesch, Greg H. ^{[1
,2
]}

Liles, John T. ^{[3
]}

Breckenridge, David G. ^{[3
]}

Nikolic-Paterson, David J. ^{[1
,2
]}

Han, Yingjie ^{[1
,2
]}

机构：

[1] Monash Med Ctr, Dept Nephrol, Clayton, Vic 3168, Australia

[2] Monash Univ, Monash Med Ctr, Ctr Inflammatory Dis, Clayton, Vic 3168, Australia

[3] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA

来源：

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE | 2018年 / 22卷 / 09期

基金：

英国医学研究理事会;

关键词：

ASK1; inflammation; JNK; macrophage; p38; MAPK; thrombosis; ACTIVATED PROTEIN-KINASE; ANTI-GBM GLOMERULONEPHRITIS; EXPERIMENTAL AUTOIMMUNE GLOMERULONEPHRITIS; INTERLEUKIN-1 RECEPTOR ANTAGONIST; RENAL INJURY; DIABETIC-NEPHROPATHY; GLOMERULAR INJURY; HALTS PROGRESSION; C-JUN; MACROPHAGES;

D O I：

10.1111/jcmm.13705

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 1hour 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-444217. In conclusion, GS-444217 treatment inhibited p38/JNK activation and development of renal injury in rat NTN. ASK1 inhibitors may have therapeutic potential in rapidly progressive glomerulonephritis.

引用

页码：4522 / 4533

页数：12