Abstract: PUB208
The Novel Kinase Inhibitor ANG3070 Improves Renal Injury in the DOCA/Salt Model of CKD
Session Information
Category: Chronic Kidney Disease (Non-Dialysis)
- 308 CKD: Mechanisms of Tubulointerstitial Fibrosis
Authors
- Oehlen, Bert, Angion Biomedica Corp., Uniondale, New York, United States
- Duan, Bin, Angion Biomedica Corp, Uniondale, New York, United States
- Zhou, Ping, Angion Biomedica Corp, Uniondale, New York, United States
- Paka, Latha, Angion Biomedica Corp, Uniondale, New York, United States
- Narayan, Prakash, Angion Biomedica Corp, Uniondale, New York, United States
- Goldberg, Itzhak D., Angion Biomedica Corp., Uniondale, New York, United States
Background
Aberrant receptor tyrosine kinase signaling has been implicated in development and progression of Chronic Kidney Disease (CKD). We investigated the effects of a novel small molecule receptor tyrosine kinase inhibitor, ANG3070, in in vitro and in vivo models of CKD.
Methods
We tested the effect of ANG3070 in vitro in TGFbeta-stimulated collagen production in renal fibroblasts (NRK49F cells) and on multiple endpoints in a co-culture system of human renal epithelial cells and fibroblasts. For in vivo studies, male Sprague-Dawley rats were uni-nephrectomized and received weekly subcutaneous injections of deoxy-corticosterone acetate (DOCA) while drinking water with 1% NaCl. After two weeks, animals were randomized to receive ANG3070 (50 mg/kg, po, bid) or vehicle. At week 6, a comprehensive panel of renal functional and histological endpoints was evaluated to assess the effect of compound treatment.
Results
ANG3070 inhibits TGFbeta-stimulated collagen production in renal fibroblasts and in a co-culture system mimicking the renal milieu, ANG3070 reduced markers of fibroblast activation (e.g. α-SMA and N-cadherin) and of fibrosis (e.g. Collagen III). Uni-nephrectomized rats treated with DOCA and salt after two weeks showed marked kidney histological damage and renal dysfunction, as shown by overt proteinuria and elevated urine levels of kidney injury marker 1 (KIM1). Compared to vehicle treated animals, treatment with ANG3070 for four weeks mitigated kidney damage and reduced renal collagen and α-SMA expression. Proteinuria, Albuminuria and urine KIM1 levels were also reduced as a result of ANG3070 treatment.
Conclusion
In preclinical experiments, the novel receptor tyrosine kinase inhibitor ANG3070 shows promise as a possible treatment for CKD.
Funding
- NIDDK Support