Collecting duct principal, but not intercalated, cell prorenin receptor regulates renal sodium and water excretion

Abstract

The collecting duct is the predominant nephron site of prorenin and prorenin receptor (PRR) expression. We previously demonstrated that the collecting duct PRR regulates epithelial Na channel (ENaC) activity and water transport; however, which cell type is involved remains unclear. Herein, we examined the effects of principal cell (PC) or intercalated cell (IC) PRR deletion on renal Na and water handling. PC or IC PRR knockout (KO) mice were obtained by crossing floxed PRR mice with mice harboring Cre recombinase under the control of the AQP2 or B1 subunit of the H ATPase promoters, respectively. PC KO mice had reduced renal medullary ENaC-α abundance and increased urinary Na losses on a low-Na diet compared with controls. Conversely, IC KO mice had no apparent differences in Na balance or ENaC abundance compared with controls. Acute treatment with prorenin increased ENaC channel number and open probability in acutely isolated cortical collecting ducts from control and IC PRR KO, but not PC PRR KO, mice. Furthermore, compared with controls, PC KO, but not IC KO mice, had increased urine volume, reduced urine osmolality, and reduced abundance of renal medullary AQP2. Taken together, these findings indicate that PC, but not IC, PRR modulates ENaC activity, urinary Na excretion, and water transport.

The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome

“…To address this question, we developed mice with principal or intercalated cell-specific deletion of the PRR. 40 Although loss of the PRR selectively in intercalated cells resulted in lower body weight, we found no effect on renal histology, medullary ENaC or aquaporin-2 expression, urineconcentrating ability, or prorenin-stimulated ENaC activity by isolated CD. In contrast, principal cell-specific PRR deletion reduced ENaC and AQP2 expression in the renal medulla, decreased urine-concentrating ability, and abolished prorenin-stimulated ENaC activity in isolated CD.…”

Low Nitric Oxide Bioavailability Increases Renin Production in the Collecting Duct

“…These findings are intriguing because in the distal nephron segments, the PRR is mostly expressed in the intercalated cells and, to lesser extend in the principal cells. Although, the PRR in the principal cells seems to be enough for the regulation of (pro)renin-mediated stimulation of Na + reabsorption via ENaC ( Ramkumar et al, 2018 ), the underlying molecular mechanisms involved remains unclear. Whether the activation of PRR by (pro)renin, but not renin, solely stimulates ENaC activity ( Lu et al, 2016 ) is a relevant functional issue that requires further investigation.…”

The (pro)renin receptor: what’s in a name?

“…lysosomal acidification and/or impaired cell homeostasis in the targeted cell types and tissues. Importantly, impairment of cell homeostasis and even slow death of PRR-deficient cells can easily be missed if researchers do not specifically look for these effects 8,9 . Therefore, it is likely that putative RAS-related phenotypes reported in mice 10,11 are influenced or even caused by impaired cell homeostasis.…”