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Relaxin inhibits renal myofibroblast differentiation via RXFP1, the nitric oxide pathway, and Smad2
Author(s) -
Mookerjee Ishanee,
Hewitson Tim D.,
Halls Michelle L.,
Summers Roger J.,
Mathai Michael L.,
Bathgate Ross A. D.,
Tregear Geoffrey W.,
Samuel Chrishan S.
Publication year - 2009
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/fj.08-120857
Subject(s) - relaxin , myofibroblast , signal transduction , endocrinology , medicine , microbiology and biotechnology , phosphorylation , nitric oxide , chemistry , nitric oxide synthase , biology , receptor , fibrosis
ABSTRACT The hormone relaxin inhibits renal myofibroblast differentiation by interfering with TGF‐β1/ Smad2 signaling. However, the pathways involved in the relaxin‐TGF‐β1/Smad2 interaction remain unknown. This study investigated the signaling mechanisms by which human gene‐2 (H2) relaxin regulates myofibroblast differentiation in vitro by examining its effects on mixed populations of fibroblasts and myofibroblasts propagated from injured rat kidneys. Cultures containing ~60–70% myofibroblasts were used to determine which relaxin receptors, G‐proteins, and signaling pathways were involved in the H2 relaxin‐mediated regulation of α‐smooth muscle actin (α‐SMA; a marker of myofibroblast differentiation). H2 relaxin only inhibited α‐SMA immunostaining and collagen concentration in the presence of relaxin family peptide receptor 1 (RXFP1). H2 relaxin also induced a transient rise in cAMP in the presence of G i/o inhibition, and a sustained increase in extracellular signal‐regulated kinase (ERK)‐1/2 phosphorylation. Furthermore, inhibition of neuronal nitric oxide synthase (nNOS), NO, and cGMP significantly blocked the inhibitory effects of relaxin on α‐SMA and Smad2 phosphorylation, while the NO inhibitor, l ‐nitroarginine methyl ester (hydrochloride) ( l ‐NAME) significantly blocked the inhibitory actions of relaxin on collagen concentration in vivo . These findings suggest that relaxin signals through RXFP1, and a nNOS‐NO‐cGMP‐dependent pathway to inhibit Smad2 phosphorylation and interfere with TGF‐β1‐mediated renal myofibroblast differentiation and collagen production.—Mookerjee, I., Hewitson, T. D., Halls, M. L., Summers, R. J., Mathai, M. L., Bathgate, R. A. D., Tregear, G. W., Samuel, C. S. Relaxin inhibits renal myofibroblast differentiation via RXFP1, the nitric oxide pathway, and Smad2. FASEB J . 23, 1219–1229 (2009)