Urinary chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1) as a tubular injury marker for early detection of cisplatin-induced nephrotoxicity

Abstract

Because of the difficulty in detecting segment-specific response in the kidney, we investigated the molecular events underlying acute kidney injury in the proximal tubules of rats with cisplatin (cis-diamminedichloroplatinum II)-induced nephrotoxicity. Microarray analysis revealed that mRNA levels of several cytokines and chemokines, such as interleukin-1beta, chemokine (C-C motif) ligand (CCL) 2, CCL20, chemokine (C-X-C motif) ligand (CXCL) 1, and CXCL10 were significantly increased after cisplatin treatment in both isolated proximal tubules and whole kidney. Interestingly, tubular CCL2 mRNA levels increased soon after cisplatin administration, whereas CCL2 mRNA levels in whole kidney first decreased and then increased. Levels of both CCL2 and kidney injury molecule-1 (KIM-1) in the whole kidney increased after cisplatin administration. Immunofluorescence analysis revealed CCL2 changes in the proximal tubular cells initially and then in the medullary interstitium. Urinary CCL2 excretion significantly increased approximately 3-fold compared with controls the day after cisplatin administration (5 mg/kg), when no changes were observed plasma creatinine and blood urea nitrogen levels. Urinary levels of KIM-1 also increased 3-fold after cisplatin administration. In addition, urinary CCL2 rather than KIM-1 increased in chronic renal failure rats after administration of low-dose cisplatin (2 mg/kg), suggesting that urinary CCL2 was selective for cisplatin-induced nephrotoxicity in renal impairment. These results indicated that the increase in cytokine and chemokine expression in renal epithelial cells might be responsible for kidney deterioration in cisplatin-induced nephrotoxicity, and that urinary CCL2 is associated with tubular injury and serves as a sensitive and noninvasive marker for the early detection of cisplatin-induced tubular injury.

Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury

“…Ramesh and Reeves (68) showed that inhibition of TNF- production protects from cisplatin-induced AKI. The exact role of MCP-1 and IL-6 is not clear, but the expression levels of both MCP-1 and IL-6 are known to directly correspond with the level of injury resulting from cisplatin treatment (69,70). Taken together, this suggests that C10 and cisplatin coadministration exacerbates the pro-inflammatory response associated with cisplatin-induced AKI, thereby, worsening kidney injury.…”

Six2creFrs2α knockout mice are a novel model of renal cystogenesis

“…Given that ectopic proximal tubular Shh and Ccl2 expression has been observed in models of acute kidney injury444546, we assessed whether Six2creFrs2αKO kidneys had ectopic expression of another bone fide marker of acute kidney injury, Kim14748. Quantitative PCR from E18.5 to P21, revealed significantly elevated levels of mutant Havcr1 (the gene that encodes Kim1) versus controls by P7 and that were exaggerated by P21 (Fig.…”

“…Given that ectopic tubular Shh and Ccl2 expression has been noted after acute kidney injury444546, we interrogated Kim1, a bone fide marker of AKI4748, and noted ectopic expression early in subsets of Six2creFrs2αKO proximal tubules. While ectopic Kim1 production has been noted in other PKD models, its expression in non-cystic renal epithelium has not to our knowledge been documented48.…”

Urinary kidney injury molecule-1 and monocyte chemotactic protein-1 are noninvasive biomarkers of cisplatin-induced nephrotoxicity in lung cancer patients

“…The expression of NGAL has been shown to be up-regulated in the kidney proximal tubule cells and urine in a murine model following ischemic or cisplatin-induced AKI [11]. In addition, recently we showed that the monocyte chemotactic protein-1 (MCP-1) levels are significantly increased in proximal tubular epithelial cells and urine following cisplatin-induced AKI in rats [12]. MCP-1 is a proinflammatory chemokine that plays a role in the recruitment of monocytes to the sites of injury and infection.…”