Kidney Injury Molecule-1 Expression in Rat Proximal Tubule after Treatment with Segment-Specific Nephrotoxicants

Abstract

Dose-response expression of kidney injury molecule-1 (KIM-1) gene in kidney cortex and its correlation with morphology and traditional biomarkers of nephrotoxicity (plasma creatinine and blood urea nitrogen, BUN) or segment-specific marker of proximal tubule injury (kidney glutamine synthetase, GSK) were studied in male rats treated with proximal tubule segment-specific nephrotoxicants. These included hexachloro-1:3-butadiene (HCBD, S(3) segment-specific), potassium dichromate (chromate, S(1)-S(2) segment-specific), and cephaloridine (Cph, S(2) segment-specific). Rats were treated with a single intraperitoneal (ip) injection of HCBD 25, 50, and 100 mg/kg, subcutaneous (sc) injection of chromate 8, 12.5, and 25 mg/kg; or ip injection of Cph 250, 500, and 1,000 mg/kg. KIM-1 gene showed a dose-dependent up-regulation induced by all segment-specific nephrotoxicants. Interestingly, magnitude of the up-regulation reflected the severity of microscopic tubular changes (degeneration, necrosis, and regeneration). Even low-severity microscopic observations were evidenced by significant gene expression changes. Furthermore, KIM-1 showed significant up-regulation even in the absence of morphological changes. In contrast, traditional and specific markers demonstrated low sensitivity or specificity. In conclusion, this study suggested KIM-1 as a sensitive molecular marker of different levels of tubular injury, and it is likely to represent a potential tool for early screening of nephrotoxicants.

Correlation of Histopathology, Urinary Biomarkers, and Gene Expression Responses Following Hexachloro-1:3-Butadiene–induced Acute Nephrotoxicity in Male Hanover Wistar Rats

“…Other investigators have demonstrated increases in urinary KIM-1 as early as 3 hr postinsult ). The present findings agree with recently published studies looking at KIM-1 gene expression in rats treated with HCBD, potassium dichromate, or cephaloridine (Chiusolo et al 2010), where KIM-1 gene expression was upregulated 48 hours after exposure, regardless of the nephrotoxicant used, but more dependent upon the target cell damaged within the nephron. Similarly, other workers have noted increases in urinary KIM-1 employing different nephrotoxicants, S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), cisplatin, and folic acid to induce renal tubular injury by a variety of pathological mechanisms (Ichimura et al 2004;Pinches et al 2012a).…”

Arsenic exposure causes epigenetic dysregulation of IL-8 expression leading to proneoplastic changes in kidney cells

“…4 and 5). KIM-1 has earlier been implicated for its role in tubular cell dedifferentiation and renal injury (Chiusolo et al, 2010). It is also associated with the renal fibrosis and kidney dysfunction and it is a non-invasive biomarker of renal disease (van Timmeren et al, 2007).…”

High intensity interval training favourably affects antioxidant and inflammation mRNA expression in early-stage chronic kidney disease

“…To assess kidney-specific damage and inflammation, kidney injury molecule-1 (KIM1) has emerged as a useful biomarker. Undetectable in normal kidneys [6], KIM1 expression is increased in damaged tubular cells [7,8], is associated with tubular necrosis [8] and INF [7], is related to the development of tubulointerstitial fibrosis [7], and is negatively correlated with renal function [7]. Free radicals and fibrosis further aggravate damaged tissue, resulting in recruitment of inflammatory cytokines that promote injury in distal tissues.…”