Regenerative and protective effects of renin cells on renal vasculature

• Applicant: Professor Dr. Vladimir Todorov
• Subject Area: Nephrology ; Anatomy and Physiology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 399229660

Renin is produced by juxtaglomerular (JG) cells in the afferent arterioles of the kidney in adulthood. The JG cells are conventionally regarded as renin cells since they are the main source of renin which is the rate-limiting factor in plasma Renin-Angiotensin System (RAS). Recently, it becomes increasingly clear that independently of their role within RAS, the renin cells are important for the functional and structural integrity of the kidney. We already developed a novel inducible triple-transgenic mouse model to study the RAS-unrelated functions of the renin cells. We established that the renin cells 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 fashion. Furthermore we deleted Gsα in JG cells. Upon binding of extracellular ligands to G protein-coupled receptors, Gsα catalyzes the intracellular production of the second messenger cAMP. We found that JG cell-specific Gsα deficiency leads to progressive kidney malfunction most prominently featured by renal microvascular endothelial injury with signs of thrombotic microangiopathy (TMA) and impaired production of VEGF in the renin cells.In the proposed project we aim to continue our studies by addressing two major issues:First, the significance of Gsα in renin cells in physiological and pathophysiological models with altered renal function will be studied. To this end, mice with induced Gsα deficiency in JG cells will be subjected to high-salt diet, RAS inhibition, severe arterial hypertension or acute renal TMA-like endothelial damage, and compared to wildtype control animals with regard to their kidney function. These experiments aim to further mechanistically explain the renal vascular phenotype of the renin cell-specific Gsα knockout mice as well as to identify new aspects of the protective and regenerative role of the renin cells. Second, the role of VEGF produced by the renin cells in the kidney will be investigated. Here, we will phenotype mice with induced deletion of VEGF in renin cells to prove if they will develop kidney damage similar the renin cell-specific Gsα-deficient mice. Furthermore, it will be studied whether renin cell-derived VEGF is protective in acute endothelial injury models.The proposed project is expected to provide further knowledge on the developing concept that the renin cells represent a unique cell niche necessary for both the physiological operation of the kidney and for its regeneration upon damage. It will also highlight the considerable regenerative potential of the mammalian kidney and support the idea that this potential could be mechanistically targeted by future therapeutic strategies.

• DFG Programme: Research Grants