Sheng Guo, Wubin Qian, Fenglai Du, Bingdi Wang, Xiaoli Wang, Yupeng Fang, Xuan Chen, Michael Benzinou, Francine M. Gregoire, Michael Staup, Keefe Chng, Yaxiong Chen, Yong-Fu Xiao, Yi-Xin (Jim) Wang
Although Type 2 Diabetes Mellitus (T2DM) is well characterized Non-Human Primate (NHP), the phenotypes of diabetic nephropathy, and its molecular mechanisms are not well studied in NHPs. Diabetic nephropathy in cynomolgus macaques with spontaneous dysmetabolism (Pre-DM, n=19) and diabetes (DM, n=20) were compared with normal controls (N, n=11). There were 9 NHPs with albuminuria (>42 mg/day) in the DM (45%), only 1 in Pre-DM and none in N group. The renal function measured by estimated glomerular filtration rate (eGFR) was not significantly different among the 3 groups, indicating that these NHPs were in an early stage of renal disease. From these NHPs, 3 N, 3 Pre-DM without albuminuria and 6 DM with albuminuria were selected for transcriptome analysis of kidney biopsies. There were 95 differentially expressed genes (DEGs) detected amongst the 3 groups, of which, 75DEGs between the N and DM related to diabetic nephropathy; 66 DEGs between the N and Pre-DM related to dysmetabolism without nephropathy; 68 DEGs between N and both Pre-DM & DM related to dsymetabolism; but only 1 nephropathy specific gene (LCT lactase) between the DM with albuminuria (DM) and Pre-DM without albuminuria; only 4 DEGs between the DM with albuminuria and both N & Pre-DM without albuminuria specific to nephropathy. Signaling pathway analysis of the relevant DEGs and encoded proteins highlighted the role of a kidney failure, renal and urological diseases, and inflammatory diseases related network, in which the most pivotal gene in this network is Tumor Necrosis Factor (TNF), indicating that nephropathy is a disease closely related to inflammation and cell death. Thus, the present study was the first detailed characterization of the diabetic nephropathy phenotypes and the kidney histopathological changes in NHPs and provided molecular insights into novel mechanisms of disease progression, potential new drug targets as well as specific diagnostic biomarkers.
