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Kidney Week

Abstract: SA-PO442

siRNA Inhibition of Lysophosphatidic Acid Receptor 1 (LPAR1) Attenuates Kidney Fibrosis and Improves Kidney Function in a Rat Model of Hypertensive CKD

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Liu, Yun, Nitto BioPharma Inc, San Diego, California, United States
  • Lee, Jingyuan, Nitto BioPharma Inc, San Diego, California, United States
  • Xia, Fengcheng, Nitto BioPharma Inc, San Diego, California, United States
  • Quimbo, Alistair Joseph C., Nitto BioPharma Inc, San Diego, California, United States
  • Yu, Xing-Xian (Scott), Nitto BioPharma Inc, San Diego, California, United States
Background

LPAR1 plays an important role in fibrosis. Its expression is upregulated in kidneys of different injuries. We developed an LPAR1 siRNA-LNP that shows a good kidney cell distribution and improves kidney fibrosis and function in diabetic and Adriamycin-induced models of CKD. Here we demonstrate these efficacies in rats of hypertensive CKD.

Methods

Dahl salt-sensitive rats were fed an 8% high-salt diet for 6 wks and then treated with the LPAR1 siRNA-LNP at 1 or 2 mpk once/wk for 4 wks. A group with an ACEi, Perindopril treatment (Tx) at 3 mpk daily and a combination Tx group was also included in one study. Kidney LPAR1 knockdown, uACR, urine KIM-1 and Cystatin C, kidney hydroxyproline (HP), the expression of the key fibrogenic and inflammatory genes and others were measured. Histological changes were determined.

Results

LPAR1 siRNA Tx caused a dose-dependent reduction in uACR ( >80% reduction at 2 mpk) ,urine KIM-1 and Cystatin C levels (both were nearly normalized at 2 mpk). The Tx also dose-dependently lowered blood pressure (systolic pressure dropped from ~176 to 142 mmHg in the 2 mpk group) and improved animal survival (~50% in control group vs 100% in 2 mpk group). The Tx significantly decreased kidney HP content. Histological analysis found that the Tx improved both glomerular and tubular histology including glomerulosclerosis and tubule-interstitial fibrosis. RNAscope analysis found that Tx at 2 mpk normalized LPAR1 expression. RNAseq analysis indicated that the Tx significantly lowered fibrogenic and inflammatory signaling activities and increased mitochondrial TCA cycle and oxidative phosphorylation activities. RT-PCR confirmed a down-regulation in expression of the key fibrogenic and inflammatory genes including TGFβ, CTGF, Col1a1, Col2a1, RAGE and NF-κβ. Though both LPAR1 siRNA and Perindopril lowered serum creatinine levels to a similar degree, LPAR1 siRNA showed a much better efficacy than the ACEi in improving kidney histology. Combination Tx showed additive effects on serum creatinine and kidney histology.

Conclusion

These data further demonstrated that siRNA inhibition of LPAR1 improves kidney fibrosis and function in rats of hypertensive CKD in addition to other models. Therefore, the LPAR1 siRNA-LNP could be a potential therapeutic for kidney fibrosis.