Modulation of cacium homeostasis may be associated with susceptibility to renal cell carcinoma in dabetic nephropathy rats

Recent observational studies have shown that diabetes mellitus increases the long-term risk of solid organ cancer development in affected patients. We analyzed in an in vivo model whether diabetic nephrology(DN)increases the risk for the development of renal cell cancer(RCC).A total of 42 male Sprague Dawley(SD)rats 9 were randomly assigned to a DN group(n=35)and a control group(n=7).All animals in the DN group were unilaterally nephrectomized and treated with streptozotocin with development of blood glucose levels>16.7mmol/L and dominant proteinuria and were compared to controls without such changes. Histopathologic alterations in the kidneys were examined(H&E staining)and differentially expressed genes were identified and validated by RNA-seq and PCR. Animals with overt signs of DN demonstrated significantly higher food and water intake, urine production, and urine protein and urinary protein/creatinine ratio than controls.Overall,14.3%(n=5/35) of DN animals developed RCCs while none cancers were observed in the control group (n=0/7).Interestingly, DN animals diagnosed with RCC showed higher GLUT2 and c-met expression. RNA-seq analysis in these animals indicated upregulated calcium signaling pathway mechanisms and regulated calcium reabsorption. Diabetic nephropathy in animals resulted in the development of renal cell suggesting that DN may contribute to carcinogenesis in the kidney putatively through altered glucose-and calcium-mediated molecular mechanisms in renal tubular cells.