Cancer Management and Research (Oct 2020)
Modulation of Calcium Homeostasis May Be Associated with Susceptibility to Renal Cell Carcinoma in Diabetic Nephropathy Rats
Abstract
Yueming Luo1,2 *,* Zhaoyu Lu1 *,* Ana Maria Waaga-Gasser,3 Haifeng Yang,4 Jialing Liu,1 Juan Wu,5 Jiayan Lu,1 Xusheng Liu,1 Lei Zhang1 1Nephrology Department, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Department of Nephrology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, People’s Republic of China; 3Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 4Department of Pathology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 5Department of Pediatrics, Guangdong Second Hospital of Chinese Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei Zhang; Xusheng Liu Tel +86-20-81887233-34330Email [email protected]; [email protected]: Clinical studies have indicated a relationship between diabetic nephropathy (DN) and the incidence and prevalence of renal cell carcinoma (RCC). However, the mechanism linking diabetic nephropathy and renal cell carcinoma has not yet to be identified.Methods: In this study, a total of 42 male Sprague Dawley (SD) rats 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 the 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 by HE staining and Ki-67 immunohistochemistry. Differentially expressed genes were identified and validated by RNA-seq and PCR.Results: As the results, except for two rats that failed to develop the DN model and were excluded from the analysis, 33 rats in the DN group 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, 15.2% (n=5/33) of DN animals developed RCC while none tumors were observed in the control group (n=0/7). RNA-seq analysis in these animals indicated different TRPV5 gene expression and calcium pathway expression in DN animals with developing tumors, when compared with animals with no obvious tumors. In addition, DN animals diagnosed with RCC showed increased expression of GLUT2 and c-met, when compared to controls and DN animals without tumors.Discussion: In conclusion, the disordered calcium metabolism, especially disturbed TRPV5 mediated Ca2+ signal, may have been related to the development of RCC in DN rats. Further studies related to the detailed mechanism are still needed.Keywords: diabetic nephropathy, renal cell carcinoma, calcium homeostasis, calcium pathway, RNA-Seq
