Treatment effects of soluble guanylate cyclase modulation on diabetic kidney disease at single-cell resolution

Diabetic kidney disease (DKD) is the most common cause of renal failure. Therapeutics development is hampered by our incomplete understanding of animal models on a cellular level. We show that ZSF1 rats recapitulate human DKD on a phenotypic and transcriptomic level. Tensor decomposition prioritizes proximal tubule (PT) and stroma as phenotype-relevant cell types exhibiting a continuous lineage relationship. As DKD features endothelial dysfunction, oxidative stress, and nitric oxide depletion, soluble guanylate cyclase (sGC) is a promising DKD drug target. sGC expression is specifically enriched in PT and stroma. In ZSF1 rats, pharmacological sGC activation confers considerable benefits over stimulation and is mechanistically related to improved oxidative stress regulation, resulting in enhanced downstream cGMP effects. Finally, we define sGC gene co-expression modules, which allow stratification of human kidney samples by DKD prevalence and disease-relevant measures such as kidney function, proteinuria, and fibrosis, underscoring the relevance of the sGC pathway to patients.糖尿病肾病（Diabetic kidney disease, DKD）是引发肾衰竭的最常见病因。当前其治疗药物的研发受到阻碍，根源在于我们对动物模型的细胞层面机制仍缺乏完整认知。本研究证实，ZSF1大鼠在表型与转录组层面可重现人类DKD的病理特征。张量分解分析筛选出近端小管（proximal tubule, PT）与肾脏基质作为表型相关细胞类型，二者呈现出连续的谱系关联。鉴于DKD具有内皮功能障碍、氧化应激及一氧化氮耗竭等病理特征，可溶性鸟苷酸环化酶（soluble guanylate cyclase, sGC）是极具潜力的DKD治疗靶点。sGC的表达在PT与肾脏基质中特异性富集。在ZSF1大鼠模型中，相较于单纯刺激干预，药物性激活sGC可带来显著获益，其作用机制与氧化应激调控改善密切相关，最终可增强下游环磷酸鸟苷（cyclic guanosine monophosphate, cGMP）的信号效应。最后，本研究明确了sGC基因共表达模块，该模块可依据DKD患病率以及肾功能、蛋白尿、纤维化等疾病相关指标对人类肾脏样本进行分层，凸显了sGC通路与DKD患者的临床相关性。