In a preclinical rat study, Lichtenberger et al. show that BAY-60-2770, a drug that activates soluble guanylyl cyclase, often rendered inactive by oxidative stress, mitigates kidney inflammation, injury, and fibrosis, likely by vascular effects after ischemia-reperfusion. Kidney perfusion, overall vascular reactivity, and medullary microvascular diameter are improved by the drug at doses that do not alter blood pressure. Soluble guanylyl cyclase is an attractive and potentially unexploited target to halt progression of chronic kidney disease.