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The anti-fibrotic hormone, relaxin, has been inferred to disrupt transforming growth factor (TGF)-β1/Smad2 phosphorylation (pSmad2) signal transduction and promote collagen-degrading gelatinase activity via a nitric oxide (NO)-dependent pathway. Here, we determined the extent to which NO, soluble guanylate cyclase (sGC) and cyclic guanosine monophosphate (cGMP) were directly involved in the anti-fibrotic actions of relaxin using a selective NO scavenger and sGC inhibitor, and comparing and combining relaxin’s effects with that of an NO donor.   Methods and Results:  Primary renal cortical myofibroblasts isolated from injured rat kidneys were treated with human recombinant relaxin (RLX; 16.8 nM), the NO donor, diethylamine NONOate (DEA/NO; 0.5–5 μM) or the combined effects of RLX (16.8 nM) and DEA/NO (5 μM) over 72 h. The effects of RLX (16.8 nM) and DEA/NO (5 μM) were also evaluated in the presence of the NO scavenger, hydroxocobalamin (HXC; 100 μM) or sGC inhibitor, ODQ (5 μM) over 72 h. Furthermore, the effects of RLX (30 nM), DEA/NO (5 μM) and RLX (30 nM) + DEA/NO (5 μM) on cGMP levels were directly measured, in the presence or absence of ODQ (5 μM). Changes in matrix metalloproteinase (MMP)-2, MMP-9 (cell media), pSmad2 and α-smooth muscle actin (α-SMA; a measure myofibroblast differentiation) (cell layer) were assessed by gelatin zymography and Western blotting, respectively. At the highest concentration tested, both RLX and DEA/NO promoted MMP-2 and MMP-9 levels by 25–33%, while inhibiting pSmad2 and α-SMA expression by up to 50% (all  p  < 0.05 vs. untreated and vehicle-treated cells). However, 5μM of DEA/NO was required to produce the effects seen with 16.8 nM of RLX over 72 h. The anti-fibrotic effects of RLX or DEA/NO alone were completely abrogated by HXC and ODQ (both  p  < 0.01 vs. RLX alone or DEA/NO alone), but were significantly enhanced when added in combination (all  p  < 0.05 vs. RLX alone). Additionally, the direct cGMP-promoting effects of RLX, DEA/NO and RLX+DEA/NO (which all increased cGMP levels by 12-16-fold over basal levels; all  p  < 0.01 vs. vehicle-treated cells) were significantly inhibited by pre-treatment of ODQ (all  p  < 0.05 vs. the respective treatments alone).   Conclusion:  These findings confirmed that RLX mediates its TGF-β1-inhibitory and gelatinase-promoting effects via a NO-sGC-cGMP-dependent pathway, which was additively augmented by co-administration of DEA/NO.

frontiers in pharmacology

The Anti-fibrotic Actions of Relaxin Are Mediated Through a NO-sGC-cGMP-Dependent Pathway in Renal Myofibroblasts In Vitro and Enhanced by the NO Donor, Diethylamine NONOate