Novel mechanism of activation of the Renin-Angiotensin-System by inflammatory cells in diabetic kidney disease

PROJECT ABSTRACT There is a critical need to identify new mechanisms and signaling pathways promoting diabetic kidney disease. Intrarenal expression of renin and pro-renin are enhanced in diabetes and blockade of the renin angiotensin system improves diabetic kidney disease (DKD) and kidney function. Pro-renin is elevated in plasma of patients and mice with type-1 diabetes and plays a role in DKD, independently from its role in blood pressure. The main source of the circulating renin and pro-renin are Juxtaglomerular Cells (JG cells) located in the afferent arteriole. Pro-inflammatory cells infiltrate the diabetic kidney cortex, increasing the release of interleukins (IL). The specific inflammatory cells and their localization in the cortex in diabetic mice is not clear. Our preliminary data shows an increased number of T lymphocytes (Th17) in kidneys from diabetic mice. Our data also show that IL17 increases renin release from JG cells and that receptors for IL17 (IL17-R) are enhanced in JG cells from diabetic mice suggesting that this pathway could be in volved in activation of the kidney renin angiotensin system in diabetes. In this exploratory grant we will identify new subpopulations of inflammatory cells in the renal cortex of diabetic mice by single cell RNA seq and mass cytometry and study their localization in the juxtaglomerular area by CyToF imaging. In addition, we will develop a triple transgenic diabetic mouse with specific deletion of IL17R in JG cells to determine the role of this pathway in DKD.