Reduction of proteinuria in adriamycin-induced nephropathy is associated with reduction of renal kidney injury molecule (Kim-1) over time.
Tubulointerstitial lesions are important in the progression of proteinuric renal disease. Tubular kidney injury molecule-1 (Kim-1) is induced in acute renal injury and reversible as a natural course. Kim-1 is also present in chronic renal damage; however, the 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 renin-angiotensin system blockade. A renal biopsy was taken 6 wk after adriamycin injection to study renal damage and Kim-1 expression. Subsequently, ACE inhibition (ACEi; n = 23), angiotensin II antagonist (AT(1A); n = 23), or vehicle (n = 10) was given for 6 wk; healthy rats served as controls (CON; n = 8). In AN, renal Kim-1 mRNA was induced 26-fold vs. CON at week 6, with further increase in vehicle to week 12 (40-fold) but was reduced by ACEi and AT(1A) to 10- and 12-fold vs. CON (P < 0.05 vs. week 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 weeks 6-12 in vehicle and decreased in ACEi- and AT(1A)-treated groups (P < 0.05). In vehicle, urinary Kim-1 was increased (P < 0.05 vs. CON), with a reduction by ACEi and AT(1A) (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 tubulointerstitial 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 tubulointerstitial processes of damage and repair.
Kramer
Andrea B
AB
Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
van Timmeren
Mirjan M
MM
Schuurs
Theo A
TA
Vaidya
Vishal S
VS
Bonventre
Joseph V
JV
van Goor
Harry
H
Navis
Gerjan
G
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism* / Q000652:urine; D004317:Doxorubicin / Q000633:toxicity; D005355:Fibrosis; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000473:pathology / Q000502:physiology*; D008297:Male; D011507:Proteinuria / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D004317:Doxorubicin; D012333:RNA, Messenger; C110936:Havcr1 protein, rat