Renal tubular epithelial cell prorenin receptor regulates blood pressure and sodium transport

Abstract

The physiological significance of the renal tubular prorenin receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na(+) excretion and investigated the signaling mechanisms by which PRR regulates Na(+) balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na(+) diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na(+) balance with normal- and low-Na(+) intake. PRR KO mice had an attenuated hypertensive response and reduced Na(+) retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na(+) channel (ENaC-α) expression. Treatment with mouse prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na(+) wasting and reduces the hypertensive response to ANG II.

Unraveling the Physiology of (Pro)Renin Receptor in the Distal Nephron

“…In agreement with this finding, Ramkumar et al observed a similar stimulatory effect of prorenin on ENaC activity in isolated split-open CD 32 . Moreover, the prorenin effect was similarly unaffected by AT1 blockade 32 . Besides the ENaC regulation at activity level, PRR also upregulates α-ENaC mRNA expression in mIMCD3 cells exposed to low salt media or AngII through serine/threonine-protein kinase-1 and phosphorylated Nedd4-2 {also known as Nedd4L (neural precursor cell-expressed developmentally downregulated gene 4-like)} 33 .…”

“…These results suggest that prorenin via PRR induces Nox4-derived ROS resulting in a direct activation of ENaC. In agreement with this finding, Ramkumar et al observed a similar stimulatory effect of prorenin on ENaC activity in isolated split-open CD 32 . Moreover, the prorenin effect was similarly unaffected by AT1 blockade 32 .…”

“…Besides the above-mentioned in vitro data, strong in vivo data from 3 independent studies all support an important role of PRR in ENaC regulation under basal and/or pathophysiological conditions 29, 32, 33 . To our surprise, PRR regulation of ENaC appears to occur only in the renal medulla but not the cortex.…”

Activation of Renal (Pro)Renin Receptor Contributes to High Fructose-Induced Salt Sensitivity

“…Emerging evidence supports an important role of renal PRR in regulation of intrarenal renin-angiotensin-system (RAS) and renal function 29–31 . On the other hand, previous studies have documented interaction between fructose metabolism and the RAS.…”

Conditional ablation of the prorenin receptor in nephron progenitor cells results in developmental programming of hypertension

“…In addition, sPRR may act independent of Ang II/Ang II receptors to induce expression and activity of the epithelial sodium channel (ENaC) in the CD, thus contributing to an increase in blood pressure via enhanced Na + reabsorption in the CD (Ramkumar et al. ).…”