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.

中文翻译：

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激活可溶性鸟苷酸环化酶可减轻缺血性肾损伤


直接激活可溶性鸟苷酸环化酶 （sGC） 能否提供肾脏保护？为了回答这个问题，我们在过渡到慢性肾病 （CKD） 的急性肾损伤 （AKI） 模型中测试了 sGC 激活剂的肾脏保护作用，该激活剂的功能独立于一氧化氮和氧化的 sGC。我们假设这种治疗将为肾脏微血管系统、肾脏血流、纤维化、炎症和肾脏损伤提供保护。在大鼠单侧缺血再灌注损伤 （IRI） 后第 3 天、第 7 天、第 14 天 （急性期） 和第 84 天 （晚期） 进行评估。缺血后，动物口服载体或 sGC 激活剂 BAY 60-2770。在载体组中，髓质微血管变窄，皮质微血管表现出肥大性向内重塑。急性损伤标志物 （Kim-1、Ngal） 的 mRNA 水平在急性期较高，但在晚期下降。急性期后肾重下降，而纤维化在第 7 天后开始。纤维化 （Col1a、Tgf-β1） 和炎症标志物 （Il-6、Tnf-α） 的丰度始终升高，伴随着单核细胞侵袭，血浆胱抑素 C 和肌酐升高。BAY 60-2770 治疗增加了组织 cGMP 浓度，扩张了肾脏微血管系统，并增强了血流和氧合。这种干预显着减轻了肾脏体重减轻、细胞损伤、纤维化和炎症。sGC 激活剂治疗后血浆胱抑素 C 和肌酐显著改善，表明功能恢复，但不能排除未受伤肾脏 GFR 可能增加超过肾脏储备。在暴露于缺氧或促纤维化 TGF-β 的培养人肾小管细胞 （HK-2 细胞） 中，BAY 60-2770 改善了病理相关基因的丰度模式。 总体而言，我们的结果表明，sGC 激活可能提供有效的肾脏保护并减弱 AKI 到 CKD 的转变。