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The inwardly rectifying K + channel K ir 5.1 ( Kcnj16 ) is essential in renal salt handling and blood pressure control. However, the underlying mechanisms are not fully understood. Here, we integrated transcriptomics and metabolomics to comprehensively profile the changes in genes and metabolites in the Dahl salt-sensitive (SS) rat lacking Kcnj16 to identify potential mechanisms. Consistent with the phenotype of knockout (KO) rats, the transcriptomic profile predicted reduced blood pressure, kidney damage, and increased ion transport. Canonical pathway analysis suggested activation of metabolic-related pathways while suppression of immune response-related pathways in KO rats. Untargeted metabolomic analysis revealed different metabolic profiles between wild-type (WT) and KO rats. Integration of transcriptomic and metabolomic profiles suggested altered tricarboxylic acid (TCA) cycle, amino acid metabolism, and reactive oxygen species (ROS) metabolism that are related to SS hypertension. In conclusion, besides increased ion transport, our data suggest suppressed immune response-related and altered metabolic-related pathways of SS rats lacking K ir 5.1., Competing Interests: The authors declare no competing interests.

Uric acid (UA) is the final metabolite in purine catabolism in humans. Previous studies have shown that the dysregulation of UA homeostasis is detrimental to cardiovascular and kidney health. The Xdh gene encodes for the Xanthine Oxidoreductase enzyme group, responsible for producing UA. To explore how hypouricemia can lead to kidney damage, we created a rat model with the genetic ablation of the Xdh gene on the Dahl salt-sensitive rat background (SS Xdh-/- ). SS Xdh-/- rats lacked UA and exhibited impairment in growth and survival. This model showed severe kidney injury with increased interstitial fibrosis, glomerular damage, crystal formation, and an inability to control electrolyte balance. Using a multi-omics approach, we highlighted that lack of Xdh leads to increased oxidative stress, renal cell proliferation, and inflammation. Our data reveal that the absence of Xdh leads to kidney damage and functional decline by the accumulation of purine metabolites in the kidney and increased oxidative stress., Competing Interests: The authors declare no competing interests.

Growing evidence suggests that renal purinergic signaling undergoes significant remodeling during pathophysiological conditions such as diabetes. This study examined the renal P2 receptor profile and ATP-mediated calcium response from podocytes in glomeruli from kidneys with type 1 or type 2 diabetic kidney disease (DKD), using type 2 diabetic nephropathy (T2DN) rats and streptozotocin-injected Dahl salt-sensitive (type 1 diabetes) rats. A dramatic increase in the ATP-mediated intracellular calcium flux in podocytes was observed in both models. Pharmacological inhibition established that P2X 4 and P2X 7 are the major receptors contributing to the augmented ATP-mediated intracellular calcium signaling in diabetic podocytes. The transition in purinergic receptor composition from metabotropic to ionotropic may disrupt intracellular calcium homeostasis in podocytes resulting in their dysfunction and potentially further aggravating DKD progression., Competing Interests: The authors declare no competing interests.