Identification of FOXI1 as a potential regulator of Kidney Injury Molecule‐1 in Cisplatin‐Induced Kidney Injury

Abstract

Tracking the nephrotoxic side effects of clinically available drugs, such as the chemotherapeutic cisplatin, is important for determining the dose and duration over which they may be used. Kidney Injury Molecule 1 (KIM-1) is emerging as an important measure of drug induced kidney injury (DIKI) as is more sensitive and more accurate than currently available DIKI markers. DIKI results in elevated KIM-1 mRNA, however the factors driving KIM-1 transcription are as of yet unknown. To identify KIM-1-inducing transcription factors we used a model of cisplatin induced nephrotoxicity examining mRNA from 54 rats following cisplatin treatment. Genes induced by cisplatin in KIM-1-like expression patterns were grouped together to identify common regulatory elements. We probed the promoters of KIM-1 and similar genes for transcription factor binding sites that were statistically over-represented and identified the transcription factor forkhead box I1 (FOXI1) binding sites as significantly enriched. FOXI1 is expressed exclusively in the kidney and is critical in nephron differentiation. Interestingly, many FOXI1 targets showed significant changes in expression following cisplatin treatment, suggesting that its function is indeed altered in DIKI. Together, these data suggest a possible role for FOXI1 in driving KIM-1 expression in response to cisplatin-induced kidney injury. Funded by AstraZeneca.