{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:44:34Z","timestamp":1790905474454,"version":"4.1.0"},"reference-count":46,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[2011,9]]},"abstract":"<jats:p> Two major factors which regulate tubuloglomerular feedback (TGF)-mediated constriction of the afferent arteriole are release of superoxide (O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup>) and nitric oxide (NO) by macula densa (MD) cells. MD O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup> inactivates NO; however, among the factors that increase MD O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup> release, the role of aldosterone is unclear. We hypothesize that aldosterone activates the mineralocorticoid receptor (MR) on MD cells, resulting in increased O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup> production due to upregulation of cyclooxygenase-1 (COX-2) and NOX-2, and NOX-4, isoforms of NAD(P)H oxidase. Studies were performed on MMDD1 cells, a renal epithelial cell line with properties of MD cells. RT-PCR and Western blotting confirmed the expression of MR. Aldosterone (10<jats:sup>\u22128<\/jats:sup> mol\/l for 30 min) doubled MMDD1 cell O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup> production, and this was completely blocked by MR inhibition with 10<jats:sup>\u22125<\/jats:sup> mol\/l eplerenone. RT-PCR, real-time PCR, and Western blotting demonstrated aldosterone-induced increases in COX-2, NOX-2, and NOX-4 expression. Inhibition of COX-2 (NS398), NADPH oxidase (apocynin), or a combination blocked aldosterone-induced O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup> production to the same degree. These data suggest that aldosterone-stimulated MD O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup> production is mediated by COX-2 and NADPH oxidase. Next, COX-2 small-interfering RNA (siRNA) specifically decreased COX-2 mRNA without affecting NOX-2 or NOX-4 mRNAs. In the presence of the COX-2 siRNA, the aldosterone-induced increases in COX-2, NOX-2, and NOX-4 mRNAs and O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup> production were completely blocked, suggesting that COX-2 causes increased expression of NOX-2 and NOX-4. In conclusion 1) MD cells express MR; 2) aldosterone increases O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup> production by activating MR; and 3) aldosterone stimulates COX-2, which further activates NOX-2 and NOX-4 and generates O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup>. The resulting balance between O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup> and NO in the MD is important in modulating TGF. <\/jats:p>","DOI":"10.1152\/ajprenal.00596.2010","type":"journal-article","created":{"date-parts":[[2011,1,27]],"date-time":"2011-01-27T01:35:58Z","timestamp":1296092158000},"page":"F529-F535","source":"Crossref","is-referenced-by-count":30,"title":["Aldosterone stimulates superoxide production in macula densa cells"],"prefix":"10.1152","volume":"301","author":[{"given":"Xiaolong","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Cardiac Surgery, Shadong Provincial Hospital, Shandong University, Jinan, China; and"},{"name":"Department of Physiology and Biophysics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"R. 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