Journal
HYPERTENSION
Volume 61, Issue 2, Pages 443-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.112.196303
Keywords
cyclooxygenase-2; (pro)renin receptor; collecting duct; MAPK; ERK1/2
Categories
Funding
- National Institutes of Health (NIH) through the Institutional Developmental Award Program of the National Center for Research Resources [P20RR-017659, HL26371]
- American Heart Association (AHA) [09BGIA2280440]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [K12HD043451]
- PFB, Chile [12-2007]
- FONDECYT, Chile [1080590]
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During renin-angiotensin system activation, cyclooxygenase-2 (COX-2)-derived prostaglandins attenuate the pressor and antinatriuretic effects of angiotensin II (AngII) in the renal medulla. The (pro)renin receptor (PRR) is abundantly expressed in the collecting ducts (CD) and its expression is augmented by AngII. PRR overexpression upregulates COX-2 via mitogen-activated kinases/extracellular regulated kinases 1/2 in renal tissues; however, it is not clear whether this effect occurs independently or in concert with AngII type 1 receptor (AT(1)R) activation. We hypothesized that PRR activation stimulates COX-2 expression independently of AT(1)R in primary cultures of rat renal inner medullary cells. The use of different cell-specific immunomarkers (aquaporin-2 for principal cells, anion exchanger type 1 for intercalated type-A cells, and tenascin C for interstitial cells) and costaining for AT(1)R, COX-2, and PRR revealed that PRR and COX-2 were colocalized in intercalated and interstitial cells whereas principal cells did not express PRR or COX-2. In normal rat kidney sections, PRR and COX-2 were colocalized in intercalated and interstitial cells. In rat renal inner medullary cultured cells, treatment with AngII (100 nmol/L) increased COX-2 expression via AT(1)R. In addition, AngII and rat recombinant prorenin (100 nmol/L) treatments increased extracellular regulated kinases 1/2 phosphorylation, independently. Importantly, rat recombinant prorenin upregulated COX-2 expression in the presence of AT(1)R blockade. Inhibition of mitogen-activated kinases/extracellular regulated kinases 1/2 suppressed COX-2 upregulation mediated by either AngII or rat recombinant prorenin. Furthermore, PRR knockdown using PRR-short hairpin RNA blunted the rat recombinant prorenin-mediated upregulation of COX-2. These results indicate that COX-2 expression is upregulated by activation of either PRR or AT(1)R via mitogen-activated kinases/extracellular regulated kinases 1/2 in rat renal inner medullary cells. (Hypertension. 2013;61:443-449.) circle Online Data Supplement
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