Quinomycin A reduces cyst progression in Polycystic Kidney Disease

Radadiya, P. S.; Thornton, M. M.; Magenheimer, B.; Subramaniam, D.; Tran, P. V.; Calvet, J. P.; Wallace, D. P.; Sharma, M.

doi:10.1101/2020.10.18.344689

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bioRxiv · 10.1101/2020.10.18.344689

Quinomycin A reduces cyst progression in Polycystic Kidney Disease

Radadiya, P. S.·Thornton, M. M.·Magenheimer, B.·Subramaniam, D.·Tran, P. V.·Calvet, J. P.·Wallace, D. P.·Sharma, M.

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Abstract

Polycystic kidney disease (PKD) is a genetic disorder that affects cilia homeostasis and causes progressive growth of tubular-derived cysts within the kidney. Efforts to find safer drugs for PKD have increased in the past few years after the successful launch of tolvaptan, the first approved drug to combat autosomal dominant PKD progression. Here we investigate the effects of Quinomycin A on progression of PKD. Quinomycin A is a bis-intercalator peptide that has previously shown to be effective against cancer progression. Quinomycin A treatment decreased cyst progression of human ADPKD primary renal epithelial cells grown in a 3D collagen gel to form cysts. In an orthologous mouse model of PKD, Quinomycin A administration reduced kidney to body weight ratios, and reduced cystogenesis. This was accompanied by decreased cell proliferation and fibrosis. Quinomycin treatments efficiently reduced the expression of Notch pathway proteins, RBPjk and HeyL in kidneys of PKD mice. Interestingly, Quinomycin treatments also normalized cilia lengths of collecting duct cyst-lining renal epithelia of PKD mice. This is the first preclinical study to our knowledge that demonstrates Quinomycin A has protective effects against PKD progression, in part by reducing Notch signaling and renal epithelial cilia lengths. Our findings suggest Quinomycin A has potential therapeutic value for PKD patients.

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Radadiya, P. S., Thornton, M. M., Magenheimer, B., Subramaniam, D., Tran, P. V., Calvet, J. P., Wallace, D. P., Sharma, M.. 2020-10-19. Quinomycin A reduces cyst progression in Polycystic Kidney Disease. https://doi.org/10.1101/2020.10.18.344689

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