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Fibrogenic stresses activate different mitogen‐activated protein kinase pathways in renal epithelial, endothelial or fibroblast cell populations
Author(s) -
PAT Betty K,
CUTTLE Leila,
WATTERS Dianne,
YANG Tao,
JOHNSON David W,
GOBE Glenda C
Publication year - 2003
Publication title -
nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 61
eISSN - 1440-1797
pISSN - 1320-5358
DOI - 10.1046/j.1440-1797.2003.00162.x
Subject(s) - mapk/erk pathway , microbiology and biotechnology , programmed cell death , protein kinase a , apoptosis , oxidative stress , mitogen activated protein kinase , cell growth , fibroblast , kinase , cancer research , biology , medicine , endocrinology , cell culture , biochemistry , genetics
SUMMARY: Fibrogenic stresses promote progression of renal tubulointerstitial fibrosis, disparately affecting survival, proliferation and trans ‐differentiation of intrinsic renal cell populations through ill‐defined biomolecular pathways. We investigated the effect of fibrogenic stresses on the activation of cell‐specific mitogen‐activated protein kinase (MAPK) in renal fibroblast, epithelial and endothelial cell populations. The relative outcomes (cell death, proliferation, trans ‐differentiation) associated with activation or inhibition of extracellular‐regulated protein kinase (ERK) or stress activated/c‐Jun N terminal kinase (JNK) were analysed in each renal cell population after challenge with oxidative stress (1 mmol/L H 2 O 2 ), transforming growth factor‐β1 (TGF‐β1, 10 ng/mL) or tumour necrosis factor‐α (TNF‐α, 50 ng/mL) over 0–20 h. Apoptosis increased significantly in all cell types after oxidative stress ( P < 0.05). In fibroblasts, oxidative stress caused the activation of ERK (pERK) but not JNK (pJNK). Inhibition of ERK by PD98059 supported its role in a fibroblast death pathway. In epithelial and endothelial cells, oxidative stress‐induced apoptosis was preceded by early induction of pERK, but its inhibition did not support a pro‐apoptotic role. Early ERK activity may be conducive to their survival or promote the trans ‐differentiation of epithelial cells. In epithelial and endothelial cells, oxidative stress induced pJNK acutely. Pretreatment with SP600125 (JNK inhibitor) verified its pro‐apoptotic activity only in epithelial cells. Transforming growth factor‐β1 did not significantly alter mitosis or apoptosis in any of the cell types, nor did it alter MAPK activity. Tumor necrosis factor‐α caused increased apoptosis with no associated change in MAPK activity. Our results demonstrate renal cell‐specific differences in the activation of ERK and JNK following fibrotic insult, which may be useful for targeting excessive fibroblast proliferation in chronic fibrosis.