Polyamine Catabolism and Its Role in Renal Injury and Fibrosis in Mice Subjected to Repeated Low-Dose Cisplatin Treatment

Kamyar Zahedi; Sharon Barone; Marybeth Brooks; Tracy Murray Stewart; Jackson R Foley; Ashley Nwafor; Robert A Casero Jr; Manoocher Soleimani

doi:10.3390/biomedicines12030640

Polyamine Catabolism and Its Role in Renal Injury and Fibrosis in Mice Subjected to Repeated Low-Dose Cisplatin Treatment

Biomedicines. 2024 Mar 13;12(3):640. doi: 10.3390/biomedicines12030640.

Authors

Kamyar Zahedi^{1

2}, Sharon Barone^{1

2}, Marybeth Brooks^{1

2}, Tracy Murray Stewart³, Jackson R Foley³, Ashley Nwafor³, Robert A Casero Jr³, Manoocher Soleimani^{1

2}

Affiliations

¹ Division of Nephrology, Department of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
² Research Services, New Mexico Veterans Health Care Center, Albuquerque, NM 87108, USA.
³ The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Abstract

Cisplatin, a chemotherapeutic agent, can cause nephrotoxic and ototoxic injuries. Using a mouse model of repeated low dose cisplatin (RLDC), we compared the kidneys of cisplatin- and vehicle-treated mice on days 3 (early injury phase) and 35 (late injury/recovery phase) after the final treatment. RNA-seq analyses revealed increases in the expression of markers of kidney injury (e.g., lipocalin 2 and kidney injury molecule 1) and fibrosis (e.g., collagen 1, fibronectin, and vimentin 1) in RLDC mice. In addition, we observed increased expression of polyamine catabolic enzymes (spermidine/spermine N¹-acetyltransferase, Sat1, and spermine oxidase, Smox) and decreased expression of ornithine decarboxylase (Odc1), a rate-limiting enzyme in polyamine synthesis in mice subjected to RLDC. Upon confirmation of the RNA-seq results, we tested the hypothesis that enhanced polyamine catabolism contributes to the onset of renal injury and development of fibrosis. To test our hypothesis, we compared the severity of RLDC-induced renal injury and fibrosis in wildtype (WT), Sat1-KO, and Smox-KO mice. Our results suggest that the ablation of polyamine catabolic enzymes reduces the severity of renal injury and that modulation of the activity of these enzymes may protect against kidney damage and fibrosis caused by cisplatin treatment.

Keywords: chronic kidney injury; cisplatin; fibrosis; nephrotoxicity; polyamine; polyamine catabolism.

Grants and funding

This work was supported by Dialysis Clinic Inc. Research Funds C-4149, Merit Review Award 2 I01 BX001000-10 from the Department of Research Services, Veterans Health Administration, Biomedical Research Institute of New Mexico (BRINM) Katherine Do Award 372DO, Snyder–Robinson Foundation via the Million Dollar Bike Ride of the Orphan Disease Center at the University of Pennsylvania (MDBR-20-135-SRS and MDBR-21-106-SRS), the Chan–Zuckerberg Initiative, the National Institutes of Health National Cancer Institute (R01CA204345, R01CA235963), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD110500), and the Commonwealth Foundation for Cancer Research. Manoocher Soleimani is a senior clinician scientist investigator with the Department of Veterans Health Administration. This research made use of the Fluorescence Microscopy and Cell Imaging Shared Resource, which is partially supported by the University of New Mexico (UNM) Comprehensive Cancer Center Support Grant NCIP30CA118100.