Abstract
Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during Ang II (angiotensin II) infusion. The goal of the present study was to test whether such action of PRR was mediated by sPRR (soluble PRR), generated by S1P (site-1 protease), a newly identified PRR cleavage protease. F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated Ang II-induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histidine-tagged sPRR termed as sPRR-His. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mouse cortical collecting duct cell line cells exposed for 24 hours to Ang II, Ang II + PF, or Ang II + PF + sPRR-His. Ang II-induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that S1P-derived sPRR mediates Ang II-induced hypertension through enhancement of intrarenal renin level and activation of ENaC.
Highlights
Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary αENaC and elevated blood pressure during Ang II infusion
We provided a mechanism of this phenomenon, which involves the activation of intrarenal RAS and selective stimulation of renal medullary α-ENaC expression
The study was designed to test whether S1P inhibition with PF attenuated Ang II–induced hypertension and if so further to examine whether supplement of an exogenous sPRR was able to reverse the antihypertensive action of PF
Summary
Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary αENaC and elevated blood pressure during Ang II (angiotensin II) infusion. PRR is an accessory protein (M8-9) of the vacuolar-type H+-ATPase and designated ATP6AP2.2 PRR is composed of a large N-terminal extracellular domain, a single transmembrane domain, and a short cytoplasmic domain.[3] The extracellular domain is cleaved by protease to generate a sPRR (soluble form of PRR) which is detected in biological fluids.[4] furin and ADAM19 were initially shown to be the cleavage proteases, recent reports from Nakagawa et al[5] and us[6] consistently show that S1P (site-1 protease) serves as a predominant source of sPRR both in vitro and in vivo. Recent evidence has established S1P (site-1 protease) as a predominant source of sPRR (soluble [pro] renin receptor)
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