Blood Pressure Elevation of Tubular Specific (P)RR Transgenic Mice and Lethal Tubular Degeneration due to Possible Intracellular Interactions between (P)RR and Alternative Renin Products

Sae Saigo,Hiromichi Wakui,Kouichi Tamura,Lin Chen,Tabito Kino,Kotaro Uchida,Takuya Sugawara,Kengo Azushima,Michiko Sugiyama,Tomoaki Ishigami

doi:10.3390/ijms23010302

Sae Saigo, Hiromichi Wakui + Show 8 more

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https://doi.org/10.3390/ijms23010302

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Abstract

The prorenin/renin receptor ((P)RR) is a multifunctional protein that is widely distributed in various organs. Despite intensive research for more than 20 years, this receptor has not been fully characterized. In this study, we generated mice overexpressing the tubular epithelial (P)RR gene ((P)RR-TG mice) to test the previously reported functional role of (P)RR by Ramkumar et al. in 2015 using tubular specific (P)RR KO mice. (P)RR-TG mice were maintained and analyzed in individual metabolic cages and were administered angiotensin II blocker (ARB), direct renin inhibitor (DRI), and bafilomycin, that is, vacuolar ATPase (V-ATPase) antagonist. (P)RR-TG mice were hypertensive and had alkalized urine with lower osmolality and Na+ excretion. ARB and DRI, but not bafilomycin, concurrently decreased blood pressure. Bafilomycin acidized urine of (P)RR-TG mice, or equivalently this phenomenon restored the effect of overexpressed transgene, suggesting that (P)RR functioned as a V-ATPase in renal tubules. Afterall, (P)RR-TG mice were mated with alternative renin transgenic mice (ARen2-TG), which we identified as intracellular renin previously, to generate double transgenic mice (DT-TG). Lethal renal tubular damage was observed in DT-TG mice, suggesting that intracellular renin may be a ligand for (P)RR in tubules. In summary, (P)RR did not substantially affect the tissue renin-angiotensin system (RAS) in our model of tubular specific (P)RR gene over-expression, but alternative intracellular renin may be involved in (P)RR signaling in addition to conventional V-ATPase function. Further investigations are warranted.

Highlights

The renin-angiotensin system (RAS) plays pivotal roles in the maintenance and regulation of electrolyte and water homeostasis in higher vertebrates
Using metabolic cage experiments with (P)RR-TG mice, we demonstrated that blood pressure (BP) of (P)RR-TG mice was significantly higher than that of WT mice, and administration of ARB and direct renin inhibitor (DRI) successfully reduced Systolic blood pressure (SBP) in both (P)RR-TG mice and WT mice
We previously reported on the use of intracellular renin, otherwise known as alternative renin (ARen), transgenic mice [19]

Summary

Introduction

The renin-angiotensin system (RAS) plays pivotal roles in the maintenance and regulation of electrolyte and water homeostasis in higher vertebrates. In addition to the classical RAS, which comprises angiotensinogen, renin, angiotensin-converting enzyme, and angiotensin II, Ludwig et al initially discovered ATPase H+ transporting accessory protein 2 (ATP6ap2), which is an accessory protein of membrane-bound proton pump vacuolar ATPase, in 1998 [1]. (P)RR was first identified in human kidneys and initially attracted attention in the context of tissue RAS regulation. Binding of the (P)RR to renin or prorenin activates intracellular tyrosine phosphorylation-dependent pathways in a RAS-independent manner [4–6]. This peptide did not target prorenin at all, as recent structural analysis has revealed [7,8]

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