Epidemiology, Pathophysiology and Treatment of Diabetic Nephropathy

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications & trials

Abstract

This project, in part, represents an extension of work previously reported as Project Numbers Z01 DK69037, Z01 DK069097 and Z01 DK069000. It also reports on continuation of work previously reported under Project Numbers DK069036-23, DK069063-17, and DK069100-06. All work related to diabetic kidney disease, except for the genetics of diabetic kidney disease, is now reported under this single project. In the past year, we published a study in collaboration with the University of Minnesota in which we demonstrated that adolescents with type 1 diabetes exhibit relative kidney hypoxia compared with controls and this relative hypoxia was associated with elevated albuminuria and with increased renal plasma flow, fat mass, and insulin resistance. These data suggest a potential role for kidney hypoxia in the early kidney damage of diabetes that leads to the development of diabetic kidney disease. In collaboration with the University of Michigan and Princeton University, we conducted a molecular network analysis using our kidney tissue expression data to determine how COVID-19 might disproportionately affect individuals with diabetic kidney disease. We focused on the ACE2 receptor because it is the primary cell-entry receptor for the SARS-CoV-2 virus responsible for COVID-19. We found that ACE2 expression in the kidneys was predominantly localized to proximal tubular epithelial cells and we linked ACE2 expression to innate immune response and viral entry machinery, suggesting that ACE2-coregulated proximal tubular epithelial cell expression programs in type 2 diabetes may interact with the SARS-CoV-2 infection process. Upregulation of viral infection pathways by this process could explain the higher susceptibility of patients with type 2 diabetes to severe COVID-19. In collaboration with the University of New Mexico, we conducted a post-hoc analysis of clinical trial data that linked a home-based kidney care program to greater patient involvement in the care of their chronic kidney disease. In the post-hoc analysis, we found that the effectiveness of the home-based program was most prominent in patients who also had type 2 diabetes suggesting that this program was most effective in ameliorating the progression of kidney disease attributable to diabetes. In collaboration with the University of Michigan, we reported that in American Indian patients with long-standing type 2 diabetes, neuropathy and kidney disease worsened during follow-up despite stable or improving metabolic syndrome components, suggesting that early metabolic intervention may be necessary to prevent the complications of type 2 diabetes. In collaboration with the University of Bristol, we examined IGF binding protein (IGFBP) expression in American Indians with diabetic kidney disease and identified a novel role for this protein in the regulation of podocyte function. IGFBP expression is reduced in early diabetic kidney disease in type 2 diabetes and strategies to maintain glomerular IGFBP expression may be beneficial in maintaining and preserving podocyte function in early diabetic kidney disease. In collaboration with Peking University, we combined human and mouse data to demonstrate that intracellular annexin A1 modulates the inflammatory state, suggesting that it may be a promising therapeutic approach to treating or reversing diabetic kidney disease.