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Novel AXL-specific inhibitor ameliorates kidney dysfunction through the inhibition of epithelial-to-mesenchymal transition of renal tubular cells.


ABSTRACT: Chronic kidney diseases affect more than 800 million people globally and remain a high unmet need. Various therapeutic targets are currently under evaluation in pre-clinical and clinical studies. Because the growth arrest specific gene 6 (Gas6)/AXL pathway has been implicated in the pathogenesis of kidney diseases, we generated a novel selective and potent AXL inhibitor, CH5451098, and we evaluated its efficacy and elucidated its mechanism in an NEP25 mouse model that follows the clinical course of glomerular nephritis. In this model, CH5451098 significantly ameliorated the excretion of urinary albumin and elevation of serum creatinine. Additionally, it also inhibited tubulointerstitial fibrosis and tubular damage. To elucidate the mechanism behind these changes, we analyzed the effect of CH5451098 against transforming growth factor ?1 (TGF?1) and Gas6, which is a ligand of AXL receptor, in NRK-52E renal tubular epithelial cells. CH5451098 inhibited epithelial-to-mesenchymal transition (EMT) caused by the synergistic effects of TGF?1 and Gas6 in NRK-52E cells. This inhibition was also observed in NEP25 mice. Taken together, these results suggest that CH5451098 could ameliorate kidney dysfunction in glomerular nephritis by inhibiting EMT in tubular cells. These results reveal that AXL strongly contributes to the disease progression of glomerular nephritis.

SUBMITTER: Kurata A 

PROVIDER: S-EPMC7179907 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Novel AXL-specific inhibitor ameliorates kidney dysfunction through the inhibition of epithelial-to-mesenchymal transition of renal tubular cells.

Kurata Atsuo A   Tachibana Yukako Y   Takahashi Tadakatsu T   Horiba Naoshi N  

PloS one 20200423 4


Chronic kidney diseases affect more than 800 million people globally and remain a high unmet need. Various therapeutic targets are currently under evaluation in pre-clinical and clinical studies. Because the growth arrest specific gene 6 (Gas6)/AXL pathway has been implicated in the pathogenesis of kidney diseases, we generated a novel selective and potent AXL inhibitor, CH5451098, and we evaluated its efficacy and elucidated its mechanism in an NEP25 mouse model that follows the clinical course  ...[more]

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