Pharmaceutical activation of soluble guanylate cyclase diminishes acute kidney injury progression to chronic kidney disease

After an acute kidney injury (AKI), patients face elevated morbidity and mortality rates, often progressing to chronic kidney disease (CKD). Restoring adequate blood supply can prevent renal tissue hypoxia and nephron loss. Soluble guanylate cyclase (sGC) serves as a promising target for vasodilation mediation. Our study aims to explore whether pharmacological sGC activation can enhance renal perfusion, thus mitigating hypoxic damage post-AKI.

Experiments were conducted on rats subjected to unilateral ischemia-reperfusion injury (IRI) at 3, 7, 14 (acute phase), and 84 days (late phase). Rats received daily doses of sGC activator Bay 60-2770 (1 mg/kg body weight) or vehicle. Histological, immunohistochemical analyses, and ex vivo experiments on isolated perfused renal microvessels were performed.

Vehicle-treated IRI rats exhibited kidney inflammation, fibrosis, increased expression of pro-inflammatory (Il-6, Tnf-α) and renal injury markers (Kim-1, Ngal), and reduced medullary vessel diameter with hypertrophic inward remodeling of cortical vessels in the late phase. Bay 60-2770 treatment attenuated pro-inflammatory and pro-fibrotic responses, reduced kidney weight loss, and preserved renal vascular architecture. Ex vivo investigations demonstrated positive effects of sGC activation on angiotensin and acetylcholine responses in perfused renal microvessels.

Our findings highlight the short- and long-term advantages of sGC activation in mitigating AKI and decreasing subsequent CKD risk. Additionally, our experiments offer insights into the morphological and functional dynamics during the transition from AKI to CKD.