TY - JOUR
T1 - Collecting duct prorenin receptor knockout reduces renal function, increases sodium excretion, and mitigates renal responses in ANG II-induced hypertensive mice
AU - Prieto, Minolfa C.
AU - Reverte, Virginia
AU - Mamenko, Mykola
AU - Kuczeriszka, Marta
AU - Veiras, Luciana C.
AU - Rosales, Carla B.
AU - McLellan, Matthew
AU - Gentile, Oliver
AU - Behrana Jensen, V.
AU - Ichihara, Atsuhiro
AU - McDonough, Alicia A.
AU - Pochynyuk, Oleh M.
AU - Gonzalez, Alexis A.
N1 - Funding Information:
We thank the Molecular, Imagine, and Analytical Core, as well as the Mouse Phenotyping Core of the Tulane Renal Hypertension Center of Excellence for providing the physical infrastructure to perform some of the experiments of this study. M. Kuczeriszka was a recipient of a Polish Academy of Sciences Postdoctoral Fellowship Award. The authors also acknowledge Akemi Katsurada, Dale M. Seth, and Alexander Castillo for excellent technical assistance.
Funding Information:
This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant R01 DK-104375, LACaTS Program Grant 1U54GM104940, and Tulane University School of Medicine, Faculty Research Pilot Funds (to M. Prieto); FONDECYT-Chile Grant 11121217 (to A. Gonzalez); NIDDK Grant R01 DK-083785 and American Heart Association (AHA)-Western States Affiliate Grant 15GRNT23160003 (to A. McDonough); AHA Grant 15SDG25550150 (to M. Mamenko); and NIDDK Grant R01 DK-095029 (to O. Pochynyuk). M. McLellan (medical student) was a scholar recipient of the Bourgeois and Ramadhyani Student Research Award.
Publisher Copyright:
© 2017 the American Physiological Society.
PY - 2017/12
Y1 - 2017/12
N2 - Augmented intratubular angiotensin (ANG) II is a key determinant of enhanced distal Na+ reabsorption via activation of epithelial Na+ channels (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 Na+ handling 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 (CDPRR-KO). At basal conditions, CDPRR-KO mice had decreased renal function and lower systolic BP associated with higher fractional Na+ excretion and lower ANG II levels in urine. After 14 days of ANG II infusion (400 ng·kg−1·min−1), the increases in systolic BP and diastolic BP were mitigated in CDPRR-KO mice. CDPRR-KO mice had lower abundance of cleaved αENaC and γENaC, as well as lower ANG II and rennin content in urine compared with wild-type mice. In isolated CD from CDPRR-KO mice, patch-clamp studies demonstrated that ANG IIdependent 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.
AB - Augmented intratubular angiotensin (ANG) II is a key determinant of enhanced distal Na+ reabsorption via activation of epithelial Na+ channels (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 Na+ handling 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 (CDPRR-KO). At basal conditions, CDPRR-KO mice had decreased renal function and lower systolic BP associated with higher fractional Na+ excretion and lower ANG II levels in urine. After 14 days of ANG II infusion (400 ng·kg−1·min−1), the increases in systolic BP and diastolic BP were mitigated in CDPRR-KO mice. CDPRR-KO mice had lower abundance of cleaved αENaC and γENaC, as well as lower ANG II and rennin content in urine compared with wild-type mice. In isolated CD from CDPRR-KO mice, patch-clamp studies demonstrated that ANG IIdependent 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.
KW - Blood pressure
KW - Distal tubular Na transport
KW - Prorenin
KW - Renin-angiotensin system
KW - Rennin
UR - http://www.scopus.com/inward/record.url?scp=85037059530&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00152.2017
DO - 10.1152/ajprenal.00152.2017
M3 - Article
C2 - 28814438
AN - SCOPUS:85037059530
VL - 313
SP - F1243-F1253
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
SN - 0363-6127
IS - 6
ER -