title: Kidney injury molecule-1 is up-regulated in renal epithelial cells in response to oxalate in vitro and in renal tissues in response to hyperoxaluria in vivo.
abstract: Oxalate is a metabolic end product excreted by the kidney. Mild increases in urinary oxalate are most commonly associated with Nephrolithiasis. Chronically high levels of urinary oxalate, as seen in patients with primary hyperoxaluria, are driving factor for recurrent renal stones, and ultimately lead to renal failure, calcification of soft tissue and premature death. In previous studies others and we have demonstrated that high levels of oxalate promote injury of renal epithelial cells. However, methods to monitor oxalate induced renal injury are limited. In the present study we evaluated changes in expression of Kidney Injury Molecule-1 (KIM-1) in response to oxalate in human renal cells (HK2 cells) in culture and in renal tissue and urine samples in hyperoxaluric animals which mimic in vitro and in vivo models of hyper-oxaluria. Results presented, herein demonstrate that oxalate exposure resulted in increased expression of KIM-1 m RNA as well as protein in HK2 cells. These effects were rapid and concentration dependent. Using in vivo models of hyperoxaluria we observed elevated expression of KIM-1 in renal tissues of hyperoxaluric rats as compared to normal controls. The increase in KIM-1 was both at protein and mRNA level, suggesting transcriptional activation of KIM-1 in response to oxalate exposure. Interestingly, in addition to increased KIM-1 expression, we observed increased levels of the ectodomain of KIM-1 in urine collected from hyperoxaluric rats. To the best of our knowledge our studies are the first direct demonstration of regulation of KIM-1 in response to oxalate exposure in renal epithelial cells in vitro and in vivo. Our results suggest that detection of KIM-1 over-expression and measurement of the ectodomain of KIM-1 in urine may hold promise as a marker to monitor oxalate nephrotoxicity in hyperoxaluria.
authors.affiliation: Signal Transduction and Molecular Urology Laboratory-Program in Urosciences, Division of Urology- Department of Surgery, School of Medicine, University of Colorado at Denver, Aurora, Colorado, United States of America.
authors.forename: Lakshmipathi
authors.initials: L
authors.lastname: Khandrika
authors.forename: Sweaty
authors.initials: S
authors.lastname: Koul
authors.forename: Randall B
authors.initials: RB
authors.lastname: Meacham
authors.forename: Hari K
authors.initials: HK
authors.lastname: Koul
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D002460:Cell Line; D003460:Crystallization; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D006959:Hyperoxaluria / Q000235:genetics / Q000473:pathology* / Q000652:urine; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D010070:Oxalates / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015815:Cell Adhesion Molecules; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D010070:Oxalates; D012333:RNA, Messenger; D011991:Receptors, Virus; C491143:HAVCR1 protein, human; C110936:Havcr1 protein, rat