Renal medullary cyclooxygenase-2 and (pro)renin receptor expression during angiotensin II-dependent hypertension

Abstract

The (pro)renin receptor [(P)RR] upregulates cyclooxygenase-2 (COX-2) in inner medullary collecting duct (IMCD) cells through ERK1/2. Intrarenal COX-2 and (P)RR are upregulated during chronic ANG II infusion. However, the duration of COX-2 and (P)RR upregulation has not been determined. We hypothesized that during the early phase of ANG II-dependent hypertension, membrane-bound (P)RR and COX-2 are augmented in the renal medulla, serving to buffer the hypertensinogenic and vasoconstricting effects of ANG II. In Sprague-Dawley rats infused with ANG II (0.4 μg·min(-1)·kg(-1)), systolic blood pressure (BP) increased by day 7 (162 ± 5 vs. 114 ± 10 mmHg) and continued to increase by day 14 (198 ± 15 vs. 115 ± 13 mmHg). Membrane-bound (P)RR was augmented at day 3 coincident with phospho-ERK1/2 levels, COX-2 expression, and PGE2 in the renal medulla. In contrast, membrane-bound (P)RR was reduced and COX-2 protein levels were not different from controls by day 14. In cultured IMCD cells, ANG II increased secretion of the soluble (P)RR. In anesthetized rats, COX-2 inhibition decreased the glomerular filtration rate (GFR) and renal blood flow (RBF) during the early phase of ANG II infusion without altering BP. However, at 14 days of ANG II infusions, COX-2 inhibition decreased mean arterial BP (MABP), RBF, and GFR. Thus, during the early phase of ANG II-dependent hypertension, the increased (P)RR and COX-2 expression in the renal medulla may contribute to attenuate the vasoconstrictor effects of ANG II on renal hemodynamics. In contrast, at 14 days the reductions in RBF and GFR caused by COX-2 inhibition paralleled the reduced MABP, suggesting that vasoconstrictor COX-2 metabolites contribute to ANG II hypertension.

Short-term nonpressor angiotensin II infusion stimulates sodium transporters in proximal tubule and distal nephron

“…2002; Gonzalez et al. 2014). Therefore, in our study, hypertension is not expected, and there was no pressure diuresis or natriuresis, no cardiac hypertrophy, and no change in hematocrit, thus, no evidence for acute volume expansion or hypertension, also no AngII associated reduced rate of weight gain, nor change in hematocrit, all previously reported by us and others during weeks long infusion of AngII (Crowley et al.…”

“…Data from longer AngII treatment (400 ng/kg/min × 12 days, dark gray bars, n  = 8) are summarized from Nguyen et al. (2014) and also normalized to saline-infused controls. Note : only one phosphorylated form of NCC is included as the other forms change in the same directions.…”

“…(Gonzalez et al. 2014) recently provided evidence for a transient increase in membrane bound prorenin receptor ((P)RR) in collecting ducts after 3 days of AngII (400 ng/kg/min) infusion at which point there was no significant increase in blood pressure. The increase in PRR led to a transient increase in COX2 protein and urinary PGE3 which the authors postulated may play a buffering role in counteracting the antinatriuretic and vasoconstrictive effects of AngII at this 3 day, prehypertensive time point.…”

“…By 14 days of AngII infusion, membrane bound (P)RR was reduced and COX-2 protein levels were not different from controls (Gonzalez et al. 2014). …”

Interaction of the renin angiotensin and cox systems in the kidney

“…In chronic Ang II infused mice where renin levels are suppressed, inhibition of COX-2 decreases blood pressure (16). In addition to previous reports, in early stage of Ang II-dependent hypertension, PRR and COX-2 were reported to be augmented in the renal medullary tissues and to mediate vasoconstriction effects of Ang II (55). In renal inner medullary cells, activation of PRR upregulates COX-2 expression through MAPK-ERK1/2 signaling pathway, and (PRR and COX-2) was shown to colocalize in interstial and intercalated cells.…”