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

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-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.

SUBMITTER: Amos LA

PROVIDER: S-EPMC6111820 | biostudies-other | 2018 Sep

REPOSITORIES: biostudies-other

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

Amos Liv A LA Ma Frank Y FY Tesch Greg H GH Liles John T JT Breckenridge David G DG Nikolic-Paterson David J DJ Han Yingjie Y

Journal of cellular and molecular medicine 20180711 9

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 neph ...[more]

PMID: 29998485

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Project description:IntroductionComplement activation, inflammation, and fibrosis play central roles in the mechanisms of injury in autoimmune glomerulonephritis (GN) but they are seldom assessed in epidemiologic studies. The measurement of urinary biomarkers of these pathways of injury could parallel disease activity and add clinical value beyond proteinuria.MethodsWe performed a prospective cohort study of 100 patients with focal and segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), lupus nephritis (LN), anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV), and membranoproliferative GN (MPGN) followed for 33 (18-54) months. Repeated urinary samples were collected throughout their follow-up to determine proteinuria, urinary sC5b-9, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta 1 (TGF-β1), expressed as creatinine ratios. We identified 177 periods of active and inactive disease based on current remission definitions for each disease.ResultsUrinary sC5b-9, MCP-1, and TGF-β1 were present in each disease. In periods leading to a remission, the reduction of urinary sC5b-9 was 91%, greater than for proteinuria with 76%. During inactive periods, those who did not experience a relapse maintained lower levels of biomarkers compared with those who relapsed. At that time, the increase in urinary sC5b-9 was significantly greater than the rise in proteinuria (8.5-fold increase compared with 3.2-fold) and urinary MCP-1 and TGF-β1. Using current remission definitions for each disease, thresholds for each biomarker were determined using receiver operating characteristic curves. Individuals who averaged levels below these cutoffs during their follow-up had better renal outcomes.ConclusionIn autoimmune glomerular diseases, urinary sC5b-9, MCP-1, and TGF-β1 are present and parallel disease activity and outcomes. Urinary sC5b-9 appears to be a more discerning marker of immunologic remissions and relapses.

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

Publications

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

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