Stimulation of Soluble Guanylate Cyclase Improves Renal Recovery After Relief of Unilateral Ureteral Obstruction

Abstract

The antifibrotic effects of soluble guanylate cyclase stimulation and cyclic guanosine monophosphate production have been observed in cases of anti-thy1-induced renal disease. We analyzed the action of the specific soluble guanylate cyclase stimulator BAY 41-8543 on the renal recovery phase in rats with unilateral ureteral obstruction after obstruction was relieved. Sprague-Dawley® rats underwent reversible unilateral ureteral obstruction for 5 days, after which obstruction was relieved. Rats were randomly assigned to unilateral ureteral obstruction and unilateral ureteral obstruction plus BAY 41-8543 (10 mg/kg body weight daily). Seven days after relief of obstruction we determined treatment effects on renal atrophy, apoptosis, fibrosis and nitric oxide/cyclic guanosine monophosphate signaling. Untreated obstructed rats showed mildly increased systolic blood pressure, marked tubular atrophy and apoptosis, tubulointerstitial macrophage infiltration and fibrosis. Plasma cyclic guanosine monophosphate levels were unaltered in untreated rats with obstruction while renal soluble guanylate cyclase mRNA expression was increased. BAY 41-8543 administration significantly increased plasma cyclic guanosine monophosphate, which was paralleled by significant decreases in systolic blood pressure, renal tubular diameter, apoptosis and renal macrophage infiltration. Also, soluble guanylate cyclase stimulation decreased tubulointerstitial fibrosis, as shown by tubulointerstitial volume, matrix protein accumulation, α-smooth muscle actin expression, collagen IV deposition and transforming growth factor-β1 mRNA expression. Soluble guanylate cyclase stimulation by BAY 41-8543 increases cyclic guanosine monophosphate production and subsequently enhances renal recovery after unilateral ureteral obstruction relief through an array of pathways. This finding suggests that soluble guanylate cyclase stimulation may serve as a novel treatment approach to restore or preserve renal structure and function in cases of obstructive kidney disease.