期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 291, 期 2, 页码 F456-F464出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00403.2005
关键词
tubulointerstitial damage; proximal tubular cell; proteinuria; renal pathology
资金
- NIDDK NIH HHS [R01 DK072381, DK-72381, DK-39773] Funding Source: Medline
Kim-1, a recently discovered membrane protein, is undetectable in normal kidneys but markedly induced in proximal tubules after ischemic and toxic injury. The function of Kim-1 is unclear, but it is implicated in damage/repair processes. The Kim-1 ectodomain is cleaved by metalloproteinases and detectable in urine. We studied Kim-1 in a nontoxic, nonischemic, model of tubulointerstitial damage caused by acute proteinuria. Uninephrectomized (NX) rats received daily (ip) injections of 2 g BSA (NX + BSA, n = 12) or saline (NX, n = 6) for 3 wk. Kidneys were stained for various damage markers by immunohistochemistry (IHC). Kim-1 mRNA (RT-PCR, in situ hybridization), protein ( IHC, Western blotting), and urinary Kim-1 (Luminex) were determined. Spatial relations between Kim-1 and other damage markers were studied by double labeling IHC. NX + BSA rats developed massive proteinuria (1,217 +/- 313 vs. 18 +/- 2 mg/day in NX, P < 0.001) and significant renal damage. Kim-1 mRNA was upregulated eightfold in NX + BSA (ratio Kim-1/beta-actin, 4.08 +/- 2.56 vs. 0.52 +/- 0.64 in NX, P < 0.001) and localized to damaged tubules. Kim-1 protein expression was markedly induced in NX + BSA (2.46 +/- 1.19 vs. 0.39 +/- 0.10% staining/field in NX, P < 0.001). Urinary Kim-1 was significantly elevated in NX + BSA (921 +/- 592 vs. 87 +/- 164 pg/ml in NX, P < 0.001) and correlated with tissue Kim-1 expression (r < 0.66, P < 0.02). Kim-1 protein was found at the apical membrane of dilated nephrons. Kim-1 expression was limited to areas with inflammation (M circle divide), fibrosis (alpha- smooth muscle actin), and tubular damage (osteopontin), and only occasionally with tubular dedifferentiation (vimentin). These results implicate involvement of Kim-1 in the pathogenesis of proteinuria-induced renal damage/ repair. Urinary Kim-1 levels may serve as a marker of proteinuria-induced renal damage.
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