Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib-Induced Hypertension

Background The tyrosine kinase inhibitor sunitinib causes hypertension associated with reduced nitric oxide (NO) availability, elevated renal vascular resistance, and decreased fractional sodium excretion. We tested whether (1) nitrate supplementation mitigates sunitinib-induced hypertension and NO contributes less to renal vascular resistance as well as fractional sodium excretion regulation in sunitinib-treated rats than in controls; and (2) renal soluble guanylate cyclase (sGC) is downregulated and sGC activation lowers arterial pressure in rats with sunitinib-induced hypertension. Methods and Results Arterial pressure responses to nitrate supplementation and the effects of systemic and intrarenal NO synthase (NOS) inhibition on renal hemodynamics and fractional sodium excretion were assessed in sunitinib-treated rats and controls. Renal NOS and sGC mRNA as well as protein abundances were determined by quantitative polymerase chain reaction and Western blot. The effect of the sGC activator cinaciguat on arterial pressure was investigated in sunitinib-treated rats. Nitrate supplementation did not mitigate sunitinib-induced hypertension. Endothelium-dependent reductions in renal vascular resistance were similar in control and sunitinib-treated animals without and with systemic NOS inhibition. Selective intrarenal NOS inhibition lowered renal medullary blood flow in control but not in sunitinib-treated rats without significant effects on fractional sodium excretion. Renal cortical sGC mRNA and sGC α₁-subunit protein abundance were less in sunitinib-treated rats than in controls, and cinaciguat effectively lowered arterial pressure by 15-20 mm Hg in sunitinib-treated rats. Conclusions Renal cortical sGC is downregulated in the presence of intact endothelium-dependent renal vascular resistance regulation in developing sunitinib-induced hypertension. This suggests that sGC downregulation occurs outside the renal vasculature, increases renal sodium retention, and contributes to nitrate resistance of sunitinib-induced hypertension.