The role of PGC-1alpha in repeated low-dose cisplatin-induced kidney injury and the progression to chronic kidney disease

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Project Summary: Cisplatin is a first-line chemotherapeutic for many solid organ cancer types, but its usages are limited by its nephrotoxicity. Thirty percent of patients who receive cisplatin develop acute kidney injury (AKI), which increases the risk of chronic kidney disease (CKD) and mortality. There are currently no treatment options to prevent or treat cisplatin-induced kidney injury (CDDP-KI). Cisplatin-induced kidney injury (CDDP-KI) has been extensively investigated in the past by our lab and many other labs using a single, high-dose model. However, patients are typically treated with periodic low doses of cisplatin, not a single high dose. Our lab and others have recently developed a potentially more clinically relevant model utilizing repeated low-dose cisplatin (RLDC) treatment. In this new model, mice receive 4 weekly doses of low dose cisplatin and are able to survive more than 6-months post-treatment. The RLDC model can be broken up into two phases. The repeated low-level injury phase, which consists of the four weeks of cisplatin treatment and is characterized by a mild decline in kidney function, insignificant levels of tubule cell death, inflammation, and development of fibrosis. After the injury phase, there is a progression phase that is characterized by persistent inflammation, exacerbated fibrosis, and the development of CKD. The mechanisms involved in both phases of this model remain largely unknown. The kidneys have the highest density of mitochondria per organ, second only to the heart. The majority of the reabsorption performed occurs in the renal proximal tubule epithelial cells (RPTECs). These cells are highly enriched in mitochondria and rely on fatty acid oxidation (FAO) as their many energy source. Cisplatin has been shown to disrupt FAO, and defective FAO in RPTEC is seen in other models of fibrosis. Our preliminary data suggest that the RLDC model causes a decrease in renal function, mitochondrial content, and PGC-1α. PGC- 1α is a master transcriptional regulator of mitochondrial biogenesis, fatty acid oxidation, lipogenesis, thermogenesis, and glucose metabolism. This research proposal will examine the relationship between PGC-1α expression and the development of fibrosis/CKD in both phases of the RLDC model. We hypothesize that increasing PGC-1α expression during the injury and/ or progression phases of RLDC will protect against kidney injury and prevent progression to CKD, respectively. This hypothesis will be tested with the following specific aims: Aim 1: Determine the role of PGC-1α in the injury phase of the RLDC model. We hypothesize that PGC-1α protects from RLDC-induced kidney injury and initiation of fibrosis. We will test this hypothesis by overexpressing and knocking out PGC-1α during the injury phase of the RLDC model. Aim 2: Determine the role of PGC-1α in the progression phase of the RLDC model. We hypothesize that increased PGC-1α expression following cisplatin dosing will prevent RLDC-induced fibrosis and progression to CKD. We will overexpress and knockout PGC-1α following RLDC dosing.