4.5 Article Proceedings Paper

Induction of kidney injury molecule-1 in homozygous Ren2 rats is attenuated by blockade of the renin-angiotensin system or p38 MAP kinase

期刊

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 292, 期 1, 页码 F313-F320

出版社

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00180.2006

关键词

homozygous TGR(mRen2)27; angiotensin II type 1 receptor

资金

  1. NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK039773, R37DK039773, R01DK072381, R33DK074099, R21DK074099] Funding Source: NIH RePORTER
  2. NIDDK NIH HHS [DK-72381, DK-39773, DK 74099] Funding Source: Medline

向作者/读者索取更多资源

Kidney injury molecule-1 (Kim-1) is associated with ischemic and proteinuric tubular injury; however, whether dysregulation of the reninangiotensin system (RAS) can also induce Kim-1 is unknown. We studied Kim-1 expression in homozygous Ren2 rats, characterized by renal damage through excessive RAS activation. We also investigated whether antifibrotic treatment (RAS blockade or p38 MAP kinase inhibition) would affect Kim-1 expression. At 7 wk of age, homozygous Ren2 rats received a nonhypotensive dose of candesartan (0.05 mg (.) kg(-)1 (.) day(-1) sc) or the p38 inhibitor SB-239063 (15 mg (.) kg(-1) (.) day(-1) sc) for 4 wk; untreated Ren2 and Sprague-Dawley (SD) rats served as controls. Kim-1 mRNA and protein expression were determined by quantitative PCR and immunohistochemistry, respectively, and related to markers of prefibrotic renal damage. Urinary Kim-1 was measured in 8-wk-old Ren2 and SD rats with and without angiotensin-converting enzyme inhibition (ramipril, 1 mg (.) kg(-1) (.) day(-1) in drinking water for 4 wk). Untreated Ren2 rats showed a > 20-fold increase in renal Kim-1 mRNA (expressed as Kim-1-to-GAPDH ratio): 75.5 +/- 43.6 vs. 3.1 +/- 1.0 in SD rats (P < 0.01). Candesartan and SB-239063 strongly reduced Kim-1 mRNA: 3.1 +/- 1.5 (P < 0.01) and 9.8 +/- 4.2 (P < 0.05), respectively. Kim-1 protein expression in damaged tubules paralleled mRNA expression. Kim-1 expression correlated with renal osteopontin, alpha-smooth muscle actin, and collagen III expression and with tubulointerstitial fibrosis. Damaged tubular segments expressing activated p38 also expressed Kim-1. Urinary Kim-1 was increased in Ren2 vs. SD (458 +/- 70 vs. 27 +/- 2 pg/ml, P < 0.01) rats and abolished in Ren2 rats treated with ramipril (33 +/- 5 pg/ml, P < 0.01). Kim-1 is associated with development of RAS-mediated renal damage. Antifibrotic treatment through RAS blockade or p38 MAP kinase inhibition reduced Kim-1 in the homozygous Ren2 model.

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