73 - Hydrogen sulfide counteracts angiotensin II-stimulated glomerular mesangial proliferation and matrix production via multiple mechanisms

Abstract

Hydrogen sulfide (H2S) is an endogenous gas mediator with multifaced biological functions. As one of the vasodilators, it counteracts many pathophysiological actions of Ang II in vivo, including hypertension, cardiovascular injury and renal sclerosis. Currently, it remains poorly understood as to whether H2S also affected Ang II-elicited cell responses in a blood pressure-independent way. Using the cultured glomerular mesangial cells (MCs), a major cell type contributing to glomerular sclerosis, we addressed this question. 1) In a three-dimensional (3D) MC culture system, H2S donor NaHS significantly prevented Ang II- and serum-induced reduction in gel area, suggesting a counteracting action on Ang II-induced MC constriction. 2) NaHS also significantly suppressed Ang II-stimulated MC proliferation, which was associated with potent inhibition of ERK phosphorylation. 3) NaHS abolished Ang II-induced formation of Hillock (an in vitro model of MC sclerosis mediated by TGF-β). Further analysis revealed that H2S significantly suppressed Ang II-elicited production and activation of TGF-β. 4) NaHS also potently inhibited Ang II-initiated and TGF-β-mediated epithelial-mesenchymal transition in cultured renal tubular cells, as evidenced by the reduced level of a-smooth muscle actin and elevated level of E-cadherin. 5) Using a recombinant active TGF-β1, we found that H2S cleaved the disulfide bond in the dimeric active TGF-β1 and promoted the formation of inactive TGF-β1 monomer. Collectively, our result indicates that H2S counteracted Ang II-induced MC constriction, proliferation and matrix production in a blood pressure-independent way, through mechanisms involving inhibition of ERK activation, suppression of TGF-β production, and promotion of the inactive TGF-β monomer formation. Our study thus provides novel mechanistic insight into the anti-proliferative and fibrotic actions of H2S and suggest that it could be used to treat sclerotic renal diseases.