Study on the Pathogenic Role of CDA1 in Diabetic Kidney Disease (DKD) in Diabetic Akita Mice

Background: CDA1 has been demonstrated to enhance TGF-β signaling and plays a pathogenic role in experimental diabetic kidney disease (DKD) in STZ-diabetic ApoE knockout mice. The role of CDA1 in other animal models with diabetes induced by different mechanisms is unknown and the mechanisms underlying CDA1’s actions have not been fully elucidated. In this study, the pathophysiologic role of CDA1 was investigated in the Akita mouse model of DKD, an insulin-deficient animal model, with RNA-seq analysis performed to explore potential molecular mechanisms. Methods: Metabolic and relevant renal parameters, such as glomerulosclerosis injury (GSI) index, urine albumin-to-creatinine ratio (ACR), renal mRNA and protein levels of profibrotic and proinflammatory genes, were examined in non-diabetic WT and diabetic Akita mice at the age of 16 weeks in the presence (CDA1 WT) or absence (CDA1 KO) of a functional CDA1 gene. RNA sequencing (RNA-seq) was performed using total RNA isolated from the kidney tissues of these mice (n=6/group). Results: Akita mice exhibited increased kidney injury, evidenced by elevated GSI (1.4-fold) and ACR (4-fold), as well as increased expression of both profibrotic and proinflammatory markers (2-fold). Importantly, deletion of CDA1 markedly attenuates these changes in Akita mice, leading to a notable 26.7% decrease in ACR and normalization of GSI, fibronectin gene expression, as well as protein expression levels of Collagen III and α-SMA to levels similar to non-diabetic controls. RNA-seq analysis revealed that CDA1 deletion modulates multiple signaling pathways closely associated with fibrosis, inflammation and cell cycle regulation, including the cytokine-cytokine receptor interaction pathway, complement and coagulation cascades, AGE-RAGE, TNF, chemokine, and relaxin signaling pathways. Notably, the expression levels of the p21 (Cdkn1a), a gene crucial in regulating cellular senescence, and senescence-associated secretory phenotype (SASP) expression, including TNF-α and MCP-1, were elevated in Akita mice, these parameters attenuated in Akita mice with CDA1 deletion. Conclusion: Targeting CDA1 effectively attenuated diabetes associated renal injury, as a result of reduction in the cellular senescence leading to attenuation of the profibrotic and proinflammatory pathways. Funding: Government Support – Non-U.S.