Does the adult kidney need its renin cells?

• Applicant: Professor Dr. Vladimir Todorov
• Subject Area: Anatomy and Physiology ; Nephrology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 470138795

The renin-producing cells (RPC) are located in the afferent arterioles of the kidney in adulthood. They are the source of plasma renin which is the rate-limiting factor in Renin-Angiotensin-System (RAS). Recently, it became clear that independently of their role within RAS, the RPC are important for the functional and structural integrity of the kidney. We established that the RPC serve as stem-cell-like precursor cells capable of differentiating to replace damaged intraglomerular cells after glomerular injury. The renin cell progenitor niche is also constantly refilled by fresh cells in a regulated manner. Furthermore, we found that the RPC protect the renal microvascular endothelium by producing pro-angiogenic and pro-fibrotic factors. It appears that the production of these signaling molecules in the RPC is finely tuned to maintain the normal function of the renal capillaries. However, our latest experiments surprisingly demonstrated that ablation of the renal RPC in adult mice does not lead to any major adverse kidney phenotype at basal conditions. These findings were unexpected also because upon RPC ablation the RAS should be downregulated thus resulting in hypoperfusion and circulatory disorders.Therefore in the proposed project, we aim to continue our studies on the novel functions of the RPC in the renal circulation at conditions where homeostasis is challenged.The planned experiments will address three major issues:First, the role of RPC during the physiological regulation of renin production will be studied. To this end, we will treat mice with ablated RPC with different salt diets or will modulate their angiotensin II levels. The observed changes in renal vascular function will be compared to those in wildtype control animals. Second, the kidney phenotype of mice with ablated RPC subjected to chronic stress will be investigated. We expect that the RPC would be necessary for an adequate response to stress signals because they as well as RAS in general are essential parts of the adaptive reactions of the organism.Third, we will explore the role of the RPC in the diabetic kidney. Here we will compare the renal vascular function and structure with a focus on glomerular endothelium of wildtype, RPC-ablated, and renin-deficient RPC-specific Gs-alpha knockout mice in two different models of Diabetes mellitus. Considering our findings that the RPC are protective of the renal microendothelium we suggest that animals with defective or diminished RPC may have an aggravated phenotype.With this project, we expect to shed light on the novel functions of RPC in clinically relevant pathophysiological models. The results from the proposed experiments should help to answer the question of whether the adult kidney needs its renin cells only under certain conditions to maintain its vascular homeostasis.

• DFG Programme: Research Grants