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1 Department of Pathology and Laboratory Medicine, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
2 Department of Internal Medicine, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
3 Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
4 BIOGEN Inc, Cambridge, MA, USA
5 Department of Surgery, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
* To whom correspondence should be addressed. E-mail: m.m.van.timmeren{at}path.umcg.nl.
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. Kim-1 ectodomain is cleaved by metalloproteinases and detectable in urine. We studied Kim-1 in a non-toxic, non-ischemic, model of tubulo-interstitial damage caused by acute proteinuria.
Uninephrectomised (NX) rats received daily i.p. injections of 2g BSA (NX+BSA, n=12) or saline (NX, n=6) for 3 wks. Kidneys were stained for various damage markers by immunohistochemistry (IHC). Kim-1 mRNA (RT-PCR, in-situ hybridization), protein (IHC, Western Blot), 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 (1217±313 vs 18±2 mg/day in NX, p<0.001) and significant renal damage. Kim-1 mRNA was upregulated 8-fold in NX+BSA (ratio Kim-1/
-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[[Oslash]];), fibrosis (
-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 marker of proteinuria-induced renal damage.
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