Abstract MP01: Vascular versus Tubular Renin: Role in Kidney Development

Abstract

Renin, the key regulated enzyme of the renin angiotensin system regulates blood pressure and fluid electrolyte homeostasis as well as morphogenesis of the kidney. Classically, renin is synthesized and released from juxtaglomerular cells located in the afferent arterioles at the entrance to the glomeruli. It has also been suggested that renin may also be synthesized by tubular cells. Interestingly, whole body deletion of the renin gene results in striking vascular and tubular abnormalities, hydronephrosis and a urine-concentrating defect. Given the complexity of such phenotype, it has not been possible to discriminate the relative contributions of vascular versus tubular renin. To investigate the relative contribution of renin in the vascular versus tubular compartments during kidney development we deleted renin independently in either compartment by crossing Ren1cfl/fl mice to Foxd1-cre or to Hoxb7-cre mice. We performed blood chemistries, histological analysis, immunostaining for specific cell markers, total kidney renin mRNA quantification and ELISA for renin in plasma. Vascular deletion of renin (Foxd1 lineage) resulted in neonatal mortality that could be rescued with daily injections of saline suggesting that this phenotype is due to an inability to concentrate the urine and improper medullary development. These mice showed absence of renal renin and negligible levels of plasma renin. Histologically, the kidneys had abnormal development of its arterioles, which became progressively thickened by disorganized, concentric hypertrophy of smooth muscle cells and marked hydronephrosis. On the other hand, lack of renin in the collecting ducts (Hoxb7 descendants) did not affect kidney morphology, intra-renal renin distribution, kidney renin mRNA expression or circulating renin during basal conditions or in response to a homeostatic stress such as low sodium diet. We conclude that renin generated in the renal vascular compartment is fundamental for the development and integrity of the kidney whereas the presence of renin in the collecting duct system is dispensable for normal kidney development and cannot compensate for the lack of renin in the vascular compartment. Further, the main source of circulating renin is the kidney vasculature.