Abstract: FR-PO993
A Novel, Small-Molecule Inhibitor of Ketohexokinase Attenuates Tubular Injury, Immune Cell Infiltration, and Renal Failure in Models of Acute and Chronic Kidney Injury
Session Information
- CKD: Pathobiology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Sroda, Natalie, Gilead Sciences Inc, Foster City, California, United States
- Badal, Shawn S., Gilead Sciences Inc, Foster City, California, United States
- Gomez, Ivan G., Gilead Sciences Inc, Foster City, California, United States
- Velasquez, Maile, Gilead Sciences Inc, Foster City, California, United States
- Ma, Frank Yuanfang, Monash Medical Centre Clayton, Clayton, Victoria, Australia
- Kasun, Zachary Alexander, Gilead Sciences Inc, Foster City, California, United States
- Jansa, Petr, Gilead Sciences Inc, Foster City, California, United States
- Nikolic-Paterson, David J., Monash Medical Centre Clayton, Clayton, Victoria, Australia
- Liles, John T., Gilead Sciences Inc, Foster City, California, United States
Background
Acute or chronic injury to proximal tubule cells (PTECs) causes endogenous production of fructose via the polyol pathway and increases ketohexokinase (KHK) activity. KHK activation causes sustained ATP depletion, cell death and propagation of inflammation cascades, which contributes to loss of kidney function. Here we describe the therapeutic activity of a potent small molecule inhibitor of KHK in models of kidney tubular injury.
Methods
The biochemical potency of KHK inhibitor (KHKi), GS-9328, was characterized (IC50<50nM) and then evaluated in an ischemia/reperfusion injury (IRI) mouse model (17min ischemia, 24hr reperfusion, -1hr pre-treatment; 115 mg/kg/PO BID); and in an adenine injury rat model (6 weeks 0.25% adenine in diet, 2 week treatment, 60 mg/kg/PO BID). Tubular injury was assessed by histology (PAS), Kim1 mRNA levels, infiltrating immune cells via flow cytometry, and function by serum levels of creatinine (sCr) and BUN.
Results
In the IRI model KHKi administration reduced the percentage of damaged tubules (↓28%; P<0.001) and kidney Kim1 mRNA levels (↓52%, P<0.001), and protected against renal failure based on sCr (0.23±0.05 vs veh 1.15±0.09 mg/dL) and BUN (36.8±7.9 vs veh 126.7±20.8 mg/dL). In the adenine model, the administration of KHKi began after animals had impaired kidney function (avg sCR = 0.67±0.02 vs. control diet 0.23±0.02 mg/dL). Animals treated with KHKi had significantly greater kidney function at the end of the study (sCr = 1.01±0.06 vs veh 1.26±0.06 mg/dL & BUN= 46±1.8 vs veh 59.2±3.1 mg/dL). KHKi also significantly reduced immune cell infiltration into the kidney cortex [e.g. CD45 (↓25%; P<0.05), CD8↓43%; P<0.05)] as assessed by flow cytometry. Finally, to extend translatability of these findings, we confirmed upregulation of the polyol pathway in human CKD datasets via RNA and protein levels of Aldose Reductase.
Conclusion
A novel, potent small molecule inhibitor of KHK is efficacious at preventing kidney function decline in rodent models of acute and chronic tubular injury. These data support KHK as a therapeutic target for kidney disease indications where tubular injury plays a major role.
Funding
- Commercial Support –