ZEB1 Promotes Cisplatin-Induced Nephrotoxicity and Fibrosis in a Repeated Low-Dose Model

Background: Cisplatin is a potent chemotherapeutic that induces acute kidney injury (AKI) and/ or chronic kidney disease (CKD) in 30% of patients, but there are no FDA approved drugs to prevent or treat the short or long-term sequelae. In vivo studies using a repeated low-dose cisplatin (RLDC) model revealed failed repair tubule cells undergoing partial EMT, increased M2-like macrophages (MΦ), and fibrosis. Zinc-finger E-box binding homeobox 1(ZEB1), a transcription factor, promotes EMT and MΦ polarization. ZEB1 is upregulated in the kidney following RLDC. We hypothesize that ZEB1 drives RLDC-induced nephrotoxicity via EMT & M2-like MΦ activation. Methods: Male and Female 8-week-old C57BL/6 mice with partial-global ZEB1 knockout (ZEB1+/-) and littermate wild-type (WT) controls were subjected to weekly cisplatin (7 mg/kg) or vehicle dosing for 4 weeks. At euthanasia, markers of kidney function (BUN) and injury (KIM-1) were measured. Analysis of kidney immune cells was performed via flow cytometry, EMT markers (vimentin, claudin-1) and fibrosis ( col1a1,TGF-b, a-SMA) were assessed by Western analysis and immunohistochemistry. Results: ZEB1+/- mice were partially protected from RLDC-induced kidney injury , EMT and progression to CKD as compared to WT control mice. ZEB1+/- mice had lower expression of kidney fibrotic markers (col1a1,TGF-b, a-SMA), and kidney CD206+ M2-like MΦ following RLDC as compared to WT control mice. These findings suggest ZEB1 as a critical mediator of cisplatin-induced renal pathology. Conclusion: These data demonstrate that ZEB1 partial-global knockout protects against cisplatin-induced kidney injury, EMT, MΦ infiltration, and fibrosis in the RLDC model. These data highlight that ZEB1 may be a viable therapeutic target to prevent AKI progression to CKD. Funding: NIDDK Support