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Kidney Week

Abstract: TH-PO124

An Unbiased Functional Genomic Screen Identifies Fibroblast Growth Factor 9 as a Novel Regulator of AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Bai, Yuntao, The Ohio State University , Columbus, Ohio, United States
  • Kim, Ji Young, The Ohio State University , Columbus, Ohio, United States
  • Jayne, Laura A., The Ohio State University, Columbus, Ohio, United States
  • Pabla, Navjotsingh P., The Ohio State University , Columbus, Ohio, United States
Background

Renal epithelial cell death and dysfunction are the hallmark and underlying cause of acute kidney injury (AKI), a common disorder characterized by sudden loss of renal function, high mortality and lack of therapeutic options. Identification of therapeutic strategies to prevent AKI is an essential but unmet medical need. Here we have used an unbiased functional genomic screen to identify therapeutic and druggable targets for AKI.

Methods

In this study, we carried out an unbiased siRNA-based high throughput screen (HTS) using a mouse renal tubular cell line. In this screen, 5169 druggable genomic genes (number of 384-well plates: 68; quadruplicate) were silenced in BUMPT cells and their effect on cisplatin-mediated cell death was examined by Cell Titer Glo assay. The siRNAs that significantly protected cells from cisplatin-induced cell death were selected for confirmatory secondary screens. Subsequently, by using a pharmacological inhibitor and renal tubule specific knock-out mice (GGT-Cre and FGF9 flox mice), one of the top hits from these screens was validated as a potential therapeutic target in three mouse models of AKI, namely cisplatin-, ischemia-, and rhabdomyolysis-induced AKI. In these mouse models, renal impairment was determined by accumulation of nitrogenous waste (blood urea nitrogen and serum creatinine), biomarkers of kidney injury (KIM1 and NGAL expression) and histological analysis (H&E staining and renal damage score).

Results

Our primary and confirmatory screens identified FGF9 as one of the regulators of renal cell death and injury. Infigratinib, a pan inhibitor of FGF9 receptors, mitigated kidney injury (KIM1, NGAL and renal damage score) and significantly improved renal function (blood urine nitrogen and creatinine) in three mouse AKI models (Vehicle vs. Infigratinib group, p ≤ 0.01). Furthermore, renal tubule specific FGF9 knock-out mice exhibited significant protection from AKI as compared to their control littermates.

Conclusion

Using a novel HTS mediated functional genomic screen, we have identified FGF9 associated signaling network as a crucial modulator of renal dysfunction and AKI. Proof-of-principle experiments also suggest that pharmacological or genitic inhibition of FGF9 signaling can mitigate AKI.