Abstract: TH-PO1105
TGFBR1 Inhibition Attenuates Expansion of Maladaptive Tubule Cells and Ameliorates Kidney Function Decline in the Adenine Nephropathy Mouse Model of CKD
Session Information
- CKD: Mechanisms - 1
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Badal, Shawn S., Chinook Therapeutics Canada Inc, Vancouver, British Columbia, Canada
- Kuo, Jay, Chinook Therapeutics Canada Inc, Vancouver, British Columbia, Canada
- Ragan, Seamus, Chinook Therapeutics Canada Inc, Vancouver, British Columbia, Canada
- McConnell, Mark, Chinook Therapeutics Canada Inc, Vancouver, British Columbia, Canada
- Amirzadeh, Reza, Chinook Therapeutics Canada Inc, Vancouver, British Columbia, Canada
- Oyinlola, Mariam Omobolanle, Chinook Therapeutics Canada Inc, Vancouver, British Columbia, Canada
- Nieh, Charles, Chinook Therapeutics Canada Inc, Vancouver, British Columbia, Canada
- Gruber, Ralph, Novartis AG, Basel, Basel-Stadt, Switzerland
- Nordlohne, Johannes, Evotec SE, Hamburg, Hamburg, Germany
- Bohnenpoll, Tobias, Evotec SE, Hamburg, Hamburg, Germany
- Olson, N. Eric, Chinook Therapeutics Canada Inc, Vancouver, British Columbia, Canada
Background
CKD is increasing worldwide and there is an urgent need for new therapies designed against molecular endotypes of CKD. Recently, a distinct population of maladaptive tubule (MT) cells with a unique molecular phenotype have been linked to more rapid ESRD progression and fibrosis, inflammation and tissue injury in CKD. Here, we characterize an in vivo model of renal impairment and evaluate if inhibition of TGF-β1 signaling attenuates MT cell accumulation, fibrosis, and renal function loss.
Methods
CD1 mice were randomized to control, 0.15% adenine diet or adenine diet with ALK5 inhibitor (ALK5i, SB-525334) equivalent to 60mg/kg in chow. Mice were sacrificed 4 weeks after diet initiation for endpoint analysis. Plasma and serum were collected for creatinine and blood urea nitrogen (BUN) analysis. Kidneys were harvested for assessment of fibrosis (PSR), tubular atrophy (LTL), MT marker (VCAM1) and tubular injury (PAS). Nuclei extracted from flash frozen kidneys were fixed, and barcoded libraries were prepared for single nucleus RNA-Seq.
Results
Creatinine (0.30±0.03 vs. 0.20±.01 mg/dL, p<0.05) and BUN (46.6±8.9 vs. 28.3±5.4, p<0.001) were elevated in adenine and attenuated in ALK5i animals. PSR stain (28.3±5.49 vs 4.5±2.08 %, p<0.0001) and tubular injury (20.7±3.9 vs 9.1±4.0 a.u., p<0.0001) increased following adenine diet and attenuated in ALK5i group. LTL+/VCAM1- (healthy PT), decreased in adenine diet and restored following ALK5i inhibition (13.8±6.0 vs 29.8±5.6 %, p<0.0001). LTL-/VCAM+ cells (MT cells), increased in adenine diet, and decreased after ALK5 inhibition (32.9±4.4 vs 19.3±4.5 %, p<0.0001). snRNA-Seq revealed significant expansion of MT cells with adenine diet and failed repair cells were dominant in the adenine samples compared to control (33% FR vs 0.9% FR).
Conclusion
Inhibition of TGF-β1 pathway attenuates MT cell accumulation in adenine model determined by sn-RNA-Seq and tubular staining for VCAM1 and LTL. ALK5i prevented adenine-induced tubular injury and atrophy, reduced fibrosis and kidney function loss. This study confirms induction of MT cells in the adenine model and as proof of concept that pharmacological intervention can impact accumulation of MT cells in a model of CKD.
Funding
- Commercial Support – Chinook Therapeutics, a Novartis Company