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Abstract: SA-PO240

Human Translational Data and Preclinical Models Support LPAR1 Antagonist as a Candidate Treatment for Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Sharma, Monika, Gilead Sciences Inc, Foster City, California, United States
  • Kaushik, Swati, Gilead Sciences Inc, Foster City, California, United States
  • Lopez, David, Gilead Sciences Inc, Foster City, California, United States
  • Kassa, Katie, Gilead Sciences Inc, Foster City, California, United States
  • Minto, Wesley, Gilead Sciences Inc, Foster City, California, United States
  • Hudson, Thomas E., Gilead Sciences Inc, Foster City, California, United States
  • Pandit, Shusil, Gilead Sciences Inc, Foster City, California, United States
  • Badal, Shawn S., Gilead Sciences Inc, Foster City, California, United States
  • Liles, John T., Gilead Sciences Inc, Foster City, California, United States
  • Zagorska, Anna, Gilead Sciences Inc, Foster City, California, United States
Background

LPA-LPAR1 signaling has been implicated in kidney fibrosis. LPAR1 activation promotes epithelial cell injury and myofibroblast proliferation. Lpar1-/- mice are protected from fibrosis in kidney injury models. Here we evaluate LPAR1 pathway in human DKD and effect of a small molecule antagonist of LPAR1 in vitro and in two distinct models of kidney injury.

Methods

European Renal cDNA Bank DKD datasets were used to evaluate LPAR1 expression. Small molecule LPAR1 antagonist, GS-1148569, was evaluated in vitro in kidney fibroblasts, mesangial cells, tubular epithelial cells, and in vivo in a) rat adenine model of tubulointerstitial injury (8 weeks 0.25% adenine in diet, 6 week of treatment, PO, BID) and b) a mouse db/db eNos-/- mouse model of glomerulosclerosis (10 weeks of treatment starting from week 10, PO, BID).

Results

LPAR1 mRNA expression is elevated in DKD kidney biopsies compared to healthy donors and negatively correlates with eGFR. In fibroblasts, mesangial cells and tubular epithelial cells, LPAR1 antagonist, GS-1148569 blocked LPA-induced Myocardin Related Transcription Factor A (MRTFA) nuclear translocation and profibrotic gene expression. In the rat adenine model, GS-1148569 significantly reduced plasma creatinine (1.0 ± 0.08 mg/dL vs 2.2 ± 0.22 mg/dL in vehicle), plasma BUN (37 ± 4.9 mg/dL vs 80 ± 6.8 mg/dL in vehicle), and plasma tubular injury markers, KIM1 (3.0 ± 1.3 ng/mL vs 9.6 ± 4.6 ng/mL vehicle) and NGAL (0.61 ± 0.43 µg/mL vs 1.1 ± 0.3 µg/mL in vehicle). GS-1148569 reduced tubulointerstitial fibrosis measured by Picrosirius Red (PSR) (12.5 ± 1.7 % area vs 21.7 ± 2.1% area in vehicle). In db/db eNos-/- mouse model, GS-1148569 reduced global glomerular sclerosis (6.5 ± 2.4 % glomeruli vs 26 ± 13.4 % glomeruli in vehicle) and increased GFR as assessed by FITC-sinistrin half-life change from week 10 to week 20 (-3.2 ± 3.3 min vs 2.2 ± 6.8 min in vehicle).

Conclusion

LPAR1 expression increases in DKD in correlation with disease severity. LPAR1 antagonism blocks profibrotic gene expression in fibroblasts and mesangial cells. LPAR1 antagonism preserves kidney function and halts fibrosis progression in adenine model and reduces global glomerular sclerosis in db/db eNos-/-. Altogether, LPAR1 is a promising therapeutic target for DKD.

Funding

  • Commercial Support