Activating soluble guanylyl cyclase attenuates ischemic kidney damage

Abstract

Can direct activation of soluble guanylyl cyclase (sGC) provide kidney-protection? To answer this, we tested the kidney-protective effects of a sGC activator, which functions independent of nitric oxide and with oxidized sGC, in an acute kidney injury (AKI) model with transition to chronic kidney disease (CKD). We hypothesize this treatment would provide protection of kidney microvasculature, kidney blood flow, fibrosis, inflammation, and kidney damage. Assessment took place on days three, seven, 14 (acute phase) and 84 (late phase) after unilateral ischemia reperfusion injury (IRI) in rats. Post-ischemia, animals received vehicle or the sGC activator BAY 60-2770 orally. In the vehicle group, medullary microvessels narrowed and cortical microvessels showed hypertrophic inward remodeling. The mRNA levels of acute injury markers (Kim-1, Ngal) were high in the acute phase but declined in the late phase. Kidney weight decreased after the acute phase, while fibrosis started after day seven. Abundance of fibrotic (Col1a, Tgf-β1) and inflammatory markers (Il-6, Tnf-α) remained elevated throughout, along with mononuclear cell invasion, with elevated plasma cystatin C and creatinine. BAY 60-2770 treatment increased tissue cGMP concentration, dilated kidney microvasculature, and enhanced blood flow and oxygenation. This intervention significantly attenuated kidney weight loss, cell damage, fibrosis, and inflammation. Plasma cystatin C and creatinine improved significantly with sGC activator treatment indicating functional recovery, though possible GFR increase above kidney reserve in uninjured kidneys could not be excluded. In cultured human tubular cells (HK-2 cells) exposed to hypoxia or profibrotic TGF-β, BAY 60-2770 improved abundance patterns of pathologically relevant genes. Overall, our results show that sGC activation may provide effective kidney-protection and attenuate the AKI-to-CKD transition.

Keywords: AKI; CKD; ischemia reperfusion; renal microvessel; sGC activator.