Role of Kidney Microvasculature-Secreted Factors in Neuropilin Signaling in Proximal Tubule During Diabetic Kidney Disease

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Project Summary. Diabetic kidney disease is a complication affecting more than 36% of diabetic patients in the United States. There is a medical need to minimize the impact of diabetic kidney disease since at later stages the only options for survival are dialysis or kidney transplant. The goal of this application is to characterize a molecular mechanism of cell-cell communication between kidney peritubular capillaries and proximal tubule. We propose that early in diabetes, before the decline in renal function, the documented deterioration of the kidney microvasculature interrupts the communication with proximal tubule via secreted factors, resulting in proximal tubule damage and diabetic kidney disease. Our preliminary results have identified candidate surface receptors in proximal tubule, neuropilins, that mediate cell signaling we found decreased in the Akita mouse model of type- 1 diabetes. Akita mice develop diabetes, but the progression of kidney disease is inconsistent and depends on the genetic background. We will use Akita mice on 129Sv background (129Sv/Akita) since they develop kidney disease. It is not known whether neuropilins mediate cell-cell communication between peritubular capillaries and proximal tubule and whether this is decreased in diabetes. Our central hypothesis is: “Neuropilins maintain proximal tubule epithelial phenotype by sensing secreted factors from peritubular capillaries, therefore interruption of this cell-cell communication pathway in type-1 diabetic 129Sv/Akita mice contributes to kidney damage”. In Specific Aim 1 we will determine whether decreased neuropilin signaling in proximal tubule contributes to diabetic kidney disease in 129Sv/Akita mice. In Specific Aim 2 we will determine whether decreased neuropilin-mediated cell-cell communication with peritubular endothelium impairs proximal tubule epithelial phenotype and contributes to diabetic kidney disease in 129Sv/Akita mice. To complete this proposal, we will utilize a combination of in vitro and in vivo approaches that include cutting edge techniques like intravital multiphoton imaging, in vivo gene transduction, proteomics and single-cell transcriptomics. We expect to make an impactful contribution towards better understanding the events that lead to diabetic kidney disease, providing the foundations for future therapies. Cell-cell communication pathways like the one we propose have not been considered as mechanism of diabetic kidney disease. Completing this proposal will cement this concept, therefore providing the scientific framework for a competitive future R01 proposal.