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Signaling pathways and late‐onset gene induction associated with renal mesangial cell hypertrophy
Author(s) -
Goruppi Sandro,
Bonventre Joseph V.,
Kyriakis John M.
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdf535
Subject(s) - biology , gene , muscle hypertrophy , signal transduction , mesangial cell , microbiology and biotechnology , endocrinology , medicine , kidney , genetics
In chronic diseases such as diabetes mellitus, continuous stress stimuli trigger a persistent, self‐reinforcing reprogramming of cellular function and gene expression that culminates in the pathological state. Late‐onset, stable changes in gene expression hold the key to understanding the molecular basis of chronic diseases. Renal failure is a common, but poorly understood complication of diabetes. Diabetic nephropathy begins with mesangial cell hypertrophy and hyperplasia, combined with excess matrix deposition. The vasoactive peptide endothelin promotes the mesangial cell hypertophy characteristic of diabetic nephropathy. In this study, we examined the signaling pathways and changes in gene expression required for endothelin‐induced mesangial cell hypertrophy. Transcriptional profiling identified seven genes induced with slow kinetics by endothelin. Of these, p8 , which encodes a small basic helix–loop–helix protein, was most strongly and stably induced. p8 is also induced in diabetic kidney. Mesangial cell hypertrophy and p8 induction both require activation of the ERK, JNK/SAPK and PI‐3‐K pathways. Small interfering RNA (siRNA)‐mediated RNA interference indicates that p8 is required for endothelin‐induced hypertrophy. Thus, p8 is a novel marker for diabetic renal hypertrophy.