Diabetic kidney disease (DKD) is the most common cause of renal failure. Therapeutics development for DKD is hampered by our incomplete understanding of animal models on a cellular level.

Here, we profiled >217,000 rat kidney nuclei. We show that the ZSF1 rat model recapitulated human DKD on a phenotypic and transcriptomic level. Tensor decomposition analysis prioritized proximal tubule (PT) and stroma as the most phenotype-relevant cell types, which exhibited a continuous lineage relationship.

We also compared the effect of pharmacological soluble guanylate cyclase (sGC) activation (sGCact) and stimulation (sGCstim) in ZSF1 rats. sGCact conferred considerable benefits over sGCstim, which were mechanistically related to improved oxidative stress regulation, resulting in enhanced downstream cGMP effects.