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We hypothesized that testosterone exacerbates proinflammatory TNF-\u03b1 production and proapoptotic and profibrotic signaling during renal obstruction, resulting in increased apoptotic cell death and tubulointerstitial fibrosis. To study this, male, female, castrated male, and testosterone-treated oophorectomized female rats were subjected to sham operation or 3 days of unilateral ureteral obstruction (UUO). Renal cortical tissue was then analyzed for TNF-\u03b1 production; proapoptotic caspase-8, -9, and -3 activity; apoptotic cell death; profibrotic transforming growth factor-\u03b21 production; and \u03b1-smooth muscle actin expression. In a separate arm, glomerular filtration rate (inulin clearance) was measured in rats pre- and post-UUO. Male and testosterone-treated oophorectomized female rats demonstrated a significant increase in TNF-\u03b1 production, caspase activity, apoptotic cell death, tubulointerstitial fibrosis, and renal dysfunction during UUO compared with castrated males and normal female rats subjected to the same time course of obstruction. These results demonstrate that endogenous testosterone production in normal male rats and testosterone exogenously administered to oophorectomized females significantly increases TNF production and proapoptotic and profibrotic signaling during renal obstruction, resulting in increased apoptotic cell death, tubulointerstitial fibrosis, and renal dysfunction.<\/jats:p>","DOI":"10.1152\/ajpendo.00704.2006","type":"journal-article","created":{"date-parts":[[2007,12,12]],"date-time":"2007-12-12T04:47:56Z","timestamp":1197434876000},"page":"E435-E443","source":"Crossref","is-referenced-by-count":97,"title":["Testosterone exacerbates obstructive renal injury by stimulating TNF-\u03b1 production and increasing proapoptotic and profibrotic signaling"],"prefix":"10.1152","volume":"294","author":[{"given":"Peter D.","family":"Metcalfe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Leslie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew T.","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R.","family":"Meldrum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"Hile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirstan K.","family":"Meldrum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2001.00007.x"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-2277.2002.tb00205.x"},{"key":"R3","unstructured":"Bell E.Renal Diseases.Philadelphia, PA: Lea & Febiger, 1946."},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(17)42006-4"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2001.0359k.x"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1161\/hh1001.090858"},{"key":"R7","doi-asserted-by":"crossref","unstructured":"Chertow GM, Lazarus JM, Paganini EP, Allgren RL, Lafayette RA, Sayegh MH.Predictors of mortality and the provision of dialysis in patients with acute tubular necrosis. 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