Submitted on November 15, 2007
Revised on January 26, 2009
Accepted on February 11, 2009
Reduction of proteinuria in adriamycin-induced nephropathy is associated with reduction of renal Kidney injury molecule-1 (Kim-1) over time
Andrea B. Kramer1, Mirjan M. van Timmeren2, Theo A. Schuurs1, Vishal S. Vaidya3, Joseph V. Bonventre4, Harry van Goor5, and Gerjan Navis1*
1 University Medical Center Groningen and University of Groningen
2 University Medical Center Groningen
3 Harvard Medical School
4 Brigham and Women's Hospital
5 Univ. Med. Center Groningen
* To whom correspondence should be addressed. E-mail: g.j.navis{at}int.umcg.nl.
Tubulointerstitial lesions are important in the progression of proteinuric renal disease. Tubular Kim-1 is induced in acute renal injury and reversible as a natural course. Kim-1 is also present in chronic renal damage; however dynamics of Kim-1 in chronic renal damage and effects of antiproteinuric treatment on Kim-1 are unknown. We studied Kim-1 in adriamycin nephrosis (AN) before and after RAS-blockade. A renal biopsy was taken 6 wks after adriamycin injection to study renal damage and Kim-1 expression. Subsequently, ACE-inhibition (ACEi, n=23), angiotensin II-antagonist (AT1A, n=23) or vehicle (n=10) was given for 6 wks, healthy rats served as controls (CON, n=8). In AN renal Kim-1 mRNA was induced 26-fold vs CON at wk 6, with further increase in vehicle to wk 12 (40-fold), but reduced by ACEi and AT1A to 10- and 12-fold vs CON (p<0.05 vs wk 6). Kim-1 protein was undetectable in CON; in AN it was present in brush border of dilated tubules in areas with adjacent interstitial lesions. Renal Kim-1 protein levels increased from wk 6 to 12 in vehicle and decreased in ACEi and AT1A-treated groups (p<0.05). In vehicle, urinary Kim-1 was increased (p<0.05 vs CON), with a reduction by ACEi and AT1A (p<0.05 vs vehicle). Renal and urinary Kim-1 correlated with proteinuria and interstitial damage cross-sectionally. Reductions in proteinuria and renal Kim-1 correlated, which was not associated by corresponding changes in tubulo-interstitial fibrosis. In conclusion, on longitudinal follow-up during antiproteinuric treatment increased renal Kim-1 expression is reversible in proportion to proteinuria reduction, likely reflecting reversibility of early tubular injury, supporting its potential as a biomarker for tubulo-interstitial processes of damage and repair.
