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 prox-imal 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 mecha-nistically 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, under-scoring the relevance of the sGC pathway to patients.

Automated summary

Diabetic kidney disease (DKD) is the leading cause of renal failure, and understanding animal models at the cellular level is important for therapeutic development. ZSF1 rats demonstrate similarities to human DKD on a phenotypic and transcriptomic level. Soluble guanylate cyclase (sGC), enriched in proximal tubule (PT) and stroma, shows potential as a drug target for DKD due to its role in endothelial dysfunction, oxidative stress, and nitric oxide depletion. Activation of sGC in ZSF1 rats improves oxidative stress regulation and downstream cGMP effects, suggesting its benefits for DKD treatment. Co-expression modules of sGC genes allow stratification of human kidney samples and highlight the relevance of the sGC pathway in DKD.