Abstract: SA-PO073
FGF9 Signaling Is a Crucial Regulator of AKI
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
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
Acute kidney injury (AKI), a clinical syndrome characterized by rapid loss of renal function, is associated with significant mortality and morbidity in hospitalized patients. Currently, there is no effective treatment or prophylactic approaches available for AKI. Our overarching goal is to dissect the molecular pathways underlying renal tubular cell dysfunction, and to identify drug-able targets that can be therapeutically exploited and translated into patients. Over the past decades, significant advances have been made in understanding the pathogenesis of AKI, mainly through the study of small animal models. Compelling evidence supports that renal cell death and dysfunction are the major hallmarks of AKI. However, clinical translation of these findings remains a significant barrier, in part due to the lack of drug-able targets.
Methods
An unbiased drug-able genome siRNA screen for regulators of renal epithelial cells was carried out in murine and human tubular epithelial cells. Primary screening and validation studies revealed fibroblast growth factor 9 (FGF9) as a novel regulator of renal cell death. To directly define the role of FGF9 in vivo, kidney tubule specific FGF9 knockout mice were generated. In addition, FGF9 targeted therapies (anti-FGF9 antibody or FGFR kinase inhibitor) were evaluated in multiple mouse models, namely cisplatin-, ischemia-, and rhabdomyolysis-associated AKI. Proteomic approaches were used to identify the downstream targets.
Results
Genetic ablation of FGF9 in kidney tubules ameliorated the severity of AKI in multiple mouse models. Moreover, FGF9 targeted treatment, e.g. anti-FGF9 antibody or FGF9 receptor inhibitor, significantly reduced the kidney damage and improved renal function in these models. We also found that Glutathione peroxidase 4 (GPx4) is the downstream target of FGF9-FGFR signaling during AKI.
Conclusion
Together these studies have identified a previously unknown pathway responsible for AKI pathogenesis. More importantly, our data provides strong preclinical evidence to further evaluate the use of FGF9 targeted therapy in AKI treatment.
Funding
- Other NIH Support