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Urotensin II‐Induced Store‐Operated Ca 2+ Entry Stimulates CAMKII/CREB‐Dependent Glomerular Mesangial Cell Proliferation and Extracellular Matrix Accumulation
Author(s) -
Soni Hitesh,
Adebiyi Adebowale
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.808.7
Subject(s) - urotensin ii , creb , medicine , endocrinology , chemistry , microbiology and biotechnology , endoplasmic reticulum , cell growth , biology , receptor , biochemistry , transcription factor , gene
Urotensin II (UII), a peptide hormone has been implicated in diabetic nephropathy and membranoproliferative glomerulonephritis. However, whether UII regulates glomerular mesangial cell (GMC) growth remains unknown. Here, we investigated the hypothesis that UII‐induced store‐operated Ca 2+ entry (SOCE) through plasmalemmal TRPC channels modulates GMC growth. Knockdown of STIM1, an endoplasmic reticulum‐localized Ca 2+ sensor and TRPC4, but not TRPC1 attenuated UII‐induced SOCE in murine GMCs. ML204, a TRPC4 channel blocker also inhibited UII‐induced SOCE in the cells. Real‐time imaging of GMC growth by live content microscopy indicated that UII promotes GMC proliferation. UII‐induced GMC proliferation was inhibited by urantide, a UTR antagonist, BAPTA a [Ca 2+ ] i chelator, KN‐93, a CAMKII inhibitor, and ML204. STIM1 and TRPC4, but not TRPC1 knockdown attenuated UII‐induced GMC proliferation. UII stimulated phosphorylation of CAMKII (Thr 286 ) and Ca 2+ /cAMP response element‐binding protein (CREB; Ser 133 ) in GMCs. UII also increased type IV collagen (cIV; a mesangial matrix component) secretion by the cells. UII‐induced cIV secretion was reduced by urantide, ML204, and KN‐93. Moreover, inhibition of transcriptional coactivators CREB binding protein/p300 diminished UII‐induced GMC proliferation and cIV secretion. Taken together, these data suggest that UII‐induced SOCE via TRPC4 channels stimulates CAMKII/CREB‐dependent GMC proliferation and matrix accumulation. UII‐induced GMC proliferation and cIV secretion could be of importance in glomerulopathies associated with mesangial matrix expansion.