Collecting duct prorenin receptor knockout reduces renal function, increases sodium excretion, and mitigates renal responses in ANG II-induced hypertensive mice

Aug 18, 2017American journal of physiology. Renal physiology

Removing a receptor in kidney collecting ducts lowers kidney function, increases salt loss, and reduces kidney response in mice with high blood pressure caused by angiotensin II

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Abstract

PRR-KO mice had lower systolic blood pressure associated with higher sodium excretion and lower angiotensin II levels in urine.

Increased expression of the prorenin receptor (PRR) in the collecting duct is linked to sodium transport and hypertension.
PRR deletion in the collecting duct resulted in decreased renal function and lower systolic blood pressure under basal conditions.
After 14 days of angiotensin II infusion, PRR-KO mice showed mitigated increases in both systolic and diastolic blood pressure.
PRR-KO mice had lower levels of cleaved ENaC proteins and reduced angiotensin II and renin content in urine compared to wild-type mice.
Reduced stimulation of ENaC activity in PRR-KO mice was observed, indicating fewer active channels and lower open probability.

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Augmented intratubular angiotensin (ANG) II is a key determinant of enhanced distal Nareabsorption via activation of epithelial Nachannels (ENaC) and other transporters, which leads to the development of high blood pressure (BP). In ANG II-induced hypertension, there is increased expression of the prorenin receptor (PRR) in the collecting duct (CD), which has been implicated in the stimulation of the sodium transporters and resultant hypertension. The impact of PRR deletion along the nephron on BP regulation and Nahandling remains controversial. In the present study, we investigate the role of PRR in the regulation of renal function and BP by using a mouse model with specific deletion of PRR in the CD (PRR-KO). At basal conditions,PRR-KO mice had decreased renal function and lower systolic BP associated with higher fractional Naexcretion and lower ANG II levels in urine. After 14 days of ANG II infusion (400 ng·kg·min), the increases in systolic BP and diastolic BP were mitigated inPRR-KO mice.PRR-KO mice had lower abundance of cleaved αENaC and γENaC, as well as lower ANG II and renin content in urine compared with wild-type mice. In isolated CD fromPRR-KO mice, patch-clamp studies demonstrated that ANG II-dependent stimulation of ENaC activity was reduced because of fewer active channels and lower open probability. These data indicate that CD PRR contributes to renal function and BP responses during chronic ANG II infusion by enhancing renin activity, increasing ANG II, and activating ENaC in the distal nephron segments. + + + + -1 -1CD CD CD CD CD

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Collecting duct prorenin receptor knockout reduces renal function, increases sodium excretion, and mitigates renal responses in ANG II-induced hypertensive mice

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