Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA246

Poster Communications

AT1 receptors in renal FoxD1+ stromal cells are not essential for normal kidney development

J. Schrankl1, B. Neubauer1, M. Fuchs1, K. Gerl1, A. Kurtz1, C. Wagner1

1. Physiology, University Regensburg, Regensburg, Germany.

The importance of ANGII-AT1 receptors for nephrogenesis and renal functions are well known. Specific loss of function mutations or pharmacological inhibition of ANGII-AT1 receptors can lead to severe defects in kidney development in mammals. These renal abnormalities comprise papillary and tubular atrophy, abnormal wall thickening of intrarenal arterioles, renin cell hyperplasia and impairment of urinary concentration ability. However, it is still unclear in which cell types intact ANGII-AT1 receptor signalling is essential for normal kidney development. Stroma progenitor cells which are characterized by the expression of the transcription factor FoxD1 are known to influence nephrogenesis. Furthermore, existing evidence suggests that ANGII-AT1 receptors are expressed by all cells which derive from stroma progenitor cells, such as renin producing cells, mesangial cells, tubulointerstitial cells and vascular smooth muscle cells. Therefore, we aimed to investigate the relevance of ANGII-AT1 receptors in FoxD1+ stroma progenitor cells for renal development and function. For this purpose we generated mice with a constitutive deletion of AT1a receptors in the FoxD1 lineage combined with a global AT1b receptor deletion (FoxD1+/Cre AT1fl/fl x AT1b-/-). In wildtype kidneys we found ANGII-AT1a mRNA in vascular smooth muscle cells, renin producing cells, mesangial cells and interstitial cells using in-situ hybridization. In kidneys of FoxD1+/Cre AT1fl/fl x AT1b-/- animals ANGII-AT1a mRNA could not be detected in these cells. Moreover, the typical vasoconstriction and inhibition of renin secretion after addition of ANG II to isolated perfused kidneys of wildtype kidneys were absent in kidneys of FoxD1+/Cre AT1fl/fl x AT1b-/- mice. We therefore concluded that the deletion of ANGII-AT1 receptors in FoxD1 stroma progenitor cells was very efficient. FoxD1+/Cre AT1fl/fl x AT1b-/- animals, however, showed no signs of structural or functional renal abnormalities compared to control littermates. The papilla, the walls of intrarenal arterioles as well as number and distribution of renin cells appeared normal. Glomerular filtration rates (1204±67.2 vs. 1238±89.1 µl/min per 100 g bodyweight) and systolic blood pressure (114.5±1.73 vs. 112.8±1.55 mmHg) as well as urine osmolality (1779±163.1 vs. 2134±123.9 mOsmol/l) and plasma renin concentrations (64.35±13 vs. 81.65±12 ngANG I/ml*h-1) were not significantly different in FoxD1+/Cre AT1fl/fl x AT1b-/- mice compared to control littermates. These findings suggest that ANGII-AT1 receptors in renal stromal progenitor cells and their descendants are not required for normal kidney development and renal function. Instead extrarenal ANGII-AT1 receptors in the systemic vasculature could be crucial for kidney development.

Where applicable, experiments conform with Society ethical requirements