Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA255

Poster Communications

The ETAR and ETBR in the adult murine kidney as potential factors to regulate synthesis and secretion of renin in vivo

T. H. Neder1, A. Kurtz1, C. Wagner1

1. Institute of Physiology, University of Regensburg, Regensburg, Bavaria, Germany.

Endothelin-1 is a potent renal vasoconstrictor and has been shown to inhibit renin synthesis and secretion in vitro. Among the two endothelin receptor subtypes, ET-1 is thought to mainly act through binding to endothelin-A receptors (ETAR) but has also affinity to bind specifically on endothelin-B receptors (ETBR). We were interested to examine the relevance of endothelins for the development and physiological regulation of renin secretion and synthesis in vivo, in addition if ETs bind on the ETA- and/or ETB-receptors (ETRs) following a Ca2+-dependent direct inhibiting effect on renin cells. For this purpose we generated a renin cell-specific ET-receptors knockout mouse on the basis of the Cre/loxP system (ETARflflETBRflflRenCre). The efficacy of ETRs deletion was verified by ETAR immunohistochemistry and ETBR in situ hybridization on kidney sections. In control kidneys ETAR and ETBR immunoreactivity was widely distributed in the kidney including e.g. renin cells, vascular smooth muscle cells and mesangial cells. Exclusively ETBR mRNA signal could be detected on interstitial cells. In ETARflflETBRflflRenCre kidneys both receptors immunoreactivity were lacking on renin cells only. In addition, stroma cell-specific ETRs knockout mice (FOXD1Cre/+-ETARflflETBRflfl) were generated to monitor potential indirect effects of ETs on renin synthesis and secretion. Therefore immunoreactivity of both receptors was lacking on renin cells, mesangial cells, vascular smooth muscle cells and interstitial cells in FoxD1Cre/+ animals. All mentioned ETARflflETBRflfl-Cre strains showed normally developed renin cells and had normal renin mRNA abundance, plasma renin concentrations, systolic blood pressure values, urine osmolarity and osmolytes compared to control littermates. To further investigate the role of both ETRs on renin secretion and concentration, isolated perfused kidney (ipK) was performed. All ETARflflETBRflflRenCre displayed, similar to controls, an inhibition of renin secretion through ET-1, considering this effect is due to the reduction of blood flow and not because of the decrease of renin concentration. Conversely, ipK results of FOXD1Cre/+-ETARflflETBRflfl revealed no decline of renin secretion through ET-1 with a nearly constant renal blood flow indicating that these results appeared due to absence of systemic effect in ex vivo situation. Altogether, present findings indicate that ETR isoforms located on renin cell lineage and on stroma derived cells seem to be of less relevance for renin synthesis and secretion in vivo whereas not yet addressed tubular effects or possible systemic effects are more responsible for promoting the inhibiting effect through ETs in order to equilibrate general homeostasis. In addition, the function of renal ETRs in terms of renal pathophysiology e.g. renal fibrosis, need to be evaluated prospectively.

Where applicable, experiments conform with Society ethical requirements