Stimulation of Soluble Guanylyl Cyclase (sGC) Inhibits Mesangial Cell Proliferation and Matrix Accumulation in Experimental Glomerulonephritis

Background: To date no specific treatment is established in mesangial proliferative glomerulonephritis in man. Specific stimulation of soluble guanylyl cyclase (sGC), an enzyme catalyzing the synthesis of cyclic GMP from GTP, can be achieved by the novel pyrazolopyridine derivative Bay 41-2272. In this study, we investigated the effects of sGC stimulation in experimental mesangial proliferative glomerulonephritis (anti-Thy1 model) in the rat in vivo. Methods: The effect of sGC stimulation via Bay 41-2272 on mesangial proliferation was assessed in vivo using a mesangial proliferative glomerulonephritis model in rats (anti-Thy1 model). Renal biopsies, as well as glomerular isolates, urine and blood samples were compared in Bay 41-2272 and placebo treated groups during antiThy1 nephritis. Results: The sGC β1-subunit is upregulated during anti-Thy1 nephritis and mainly confined to mesangial areas by immunohistochemistry. Specific therapeutic sGC stimulation during anti-Thy1 nephritis in vivo was achieved via Bay 41-2272 treatment as demonstrated by increased glomerular cGMP levels causing inhibition of mesangial proliferation, glomerular matrix accumulation and proteinuria compared to placebo treated animals. Conclusion: sGC is tightly regulated in glomeruli during experimental glomerulonephritis. Considering its beneficial antiproliferative, antifibrotic, and antiproteinuric effect in experimental glomerulonephritis, the therapeutic stimulation of sGC could become a promising future goal in mesangial proliferative glomerulonephritis in man.