Praliciguat, a clinical-stage soluble guanylate cyclase (sGC) stimulator, increases cGMP via the nitric oxide (NO)-sGC pathway. Praliciguat has been shown to be renoprotective in rodent models of hypertensive nephropathy and renal fibrosis. In this study, praliciguat alone and in combination with enalapril attenuated proteinuria in the obese ZSF1 rat model of diabetic nephropathy (DN). Praliciguat monotherapy did not affect hemodynamics. In contrast, enalapril monotherapy lowered blood pressure but did not attenuate proteinuria. Renal expression of genes in pathways involved in inflammation, fibrosis, oxidative stress, and kidney injury were lower in praliciguat-treated obese ZSF1 rats than in obese controls; fasting glucose and cholesterol were also lower with praliciguat treatment. To gain insight into how tubular mechanisms might contribute to its pharmacologic effects on the kidneys, we studied praliciguat's effects on pathological processes and signaling pathways in cultured human primary renal proximal tubular epithelial cells (RPTC). Praliciguat inhibited the expression of proinflammatory cytokines and secretion of monocyte chemoattractant protein 1 in tumor necrosis factor α-challenged RPTC. Praliciguat treatment also attenuated transforming growth factor β-mediated apoptosis, changes to a mesenchymal-like cellular phenotype, and phosphorylation of SMAD3 in RPTC. In conclusion, praliciguat improved proteinuria in the ZSF1 rat model of DN, and its actions in human RPTC suggest that tubular effects may contribute to its renal benefits, building upon strong evidence for the role of cGMP signaling in renal health.

中文翻译：

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Praliciguat抑制ZSF1大鼠的糖尿病肾病进展，并抑制人肾近端肾小管细胞的炎症和细胞凋亡。

临床阶段的可溶性鸟苷酸环化酶（sGC）刺激剂Praliciguat通过一氧化氮（NO）-sGC途径增加cGMP。在高血压肾病和肾纤维化的啮齿动物模型中已显示Praliciguat具有肾脏保护作用。在这项研究中，在糖尿病性肾病（DN）肥胖ZSF1大鼠模型中，单独使用普拉利瓜特联合依那普利可减轻蛋白尿。Praliciguat单一疗法未影响血液动力学。相比之下，依那普利单一疗法可降低血压，但不能减轻蛋白尿。帕拉西瓜治疗的肥胖ZSF1大鼠的肾脏中涉及炎症，纤维化，氧化应激和肾脏损伤的基因的表达低于肥胖对照组。空腹血糖和胆固醇的降低也降低了。为了深入了解肾小管机制可能如何对其肾脏产生药理作用，我们研究了培拉西瓜对培养的人原代肾近端肾小管上皮细胞（RPTC）的病理过程和信号通路的影响。Praliciguat抑制肿瘤坏死因子α挑战的RPTC中促炎细胞因子的表达和单核细胞趋化蛋白1的分泌。实用的治疗还减弱了转化生长因子β介导的凋亡，改变为间充质样细胞表型以及RPTC中SMAD3的磷酸化。总之，在cSFMP信号在肾脏健康中的作用有力的证据基础上，拉西瓜能改善DN的ZSF1大鼠模型中的蛋白尿，其在人RPTC中的作用表明肾小管作用可能有助于其肾脏益处。