CDA1(TSPYL2) Deficiency Attenuates Kidney Fibrosis and Inflammation in db/db Diabetic Mice

Background: Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease worldwide, which increases morbidity and mortality in diabetes. Targeting Cell Division Autoantigen 1 (CDA1, also known as Tspyl2) has been demonstrated to retard diabetes-associated renal injury in type1 diabetes mouse models. However, whether such beneficial effects would extend to type 2 diabetes (T2D) is unknown. Methods: This study investigated the effect of global genetic deletion of CDA1 on the development of DKD in a T2D mouse model. We generated a db/db CDA1 knockout (KO) mouse strain, assessed their kidney function and performed morphometric analysis at 16 weeks of age. To explore potential molecular mechanisms underlying the effects of CDA1 deficiency in the diabetic kidney, transcriptomic and proteomic analyses were performed on the renal cortex of these mice (n=6-10 mice/group). Results: Deletion of CDA1 significantly reduced diabetes-induced albuminuria by ~40%, and normalized mesangial expansion and collagen deposition, without affecting glucose, body weight, or lipid levels. The expression levels of renal profibrotic and proinflammatory genes were increased in the db/db diabetic mice, such as collagens I, III and IV, fibronectin, alpha-smooth muscle actin, vascular cell adhesion molecule 1, monocyte chemoattractant protein 1, tumour necrosis factor-alpha and interleukin 6. These diabetes-induced changes were attenuated in db/db CDA1 KO diabetic mice to levels similar to those seen in non-diabetic db/h control mice. As observed in the previous studies using STZ-diabetes models, CDA1 deficiency reduced the gene expression levels of TGF-β ligands and its receptors in the diabetic kidney. These results demonstrate the anti-fibrotic and anti-inflammatory effects of CDA1 deletion. Transcriptomic and proteomic analyses confirmed these effects and revealed underlying potentially injurious pathways, such as the TGF-β and NFκB pathways, as well as complement/coagulation cascades, cellular senescence and other relevant pathways. Conclusion: These results demonstrate the efficacy of targeting CDA1 in reducing renal injury as seen by targeting relevant proinflammatory and profibrotic pathways in the T2D model of db/db mice, thereby confirming that CDA1 is a promising therapeutic target for DKD in T2D. Funding: Government Support – Non-U.S.