Circadian clock disruption and growth of kidney cysts in autosomal dominant polycystic kidney disease.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the and genes, and often progresses to kidney failure. ADPKD progression is not uniform among patients, suggesting that factors secondary to the gene mutation could regulate the rate of disease progression. Here we tested the effect of circadian clock disruption on ADPKD progression. Circadian rhythms are regulated by cell-autonomous circadian clocks composed of clock proteins. BMAL1 is a core constituent of the circadian clock.

Methods: To disrupt the circadian clock, we deleted gene in the renal collecting ducts of the (RC/RC) mouse model of ADPKD (RC/RC; ; , called DKO mice), and in knockout mouse inner medullary collecting duct cells ( KO mIMCD3 cells). Only male mice were used.

Results: Human nephrectomy ADPKD kidneys and KO mIMCD3 cells showed reduced gene expression compared to normal controls. When compared to RC/RC kidneys, DKO kidneys showed significantly altered clock gene expression, increased cyst growth, cell proliferation, apoptosis and fibrosis. DKO kidneys also showed increased lipogenesis and cholesterol synthesis-related gene expression, and increased tissue triglyceride levels compared to RC/RC kidneys. Similarly, KO cells showed altered clock genes, increased lipogenesis and cholesterol synthesis-related genes, and reduced fatty-acid oxidation-related gene expression compared to cells. The KO cells showed increased cell proliferation compared to cells, which was rescued by pharmacological inhibition of lipogenesis.

Conclusion: Renal collecting duct specific gene deletion disrupts the circadian clock and triggers accelerated ADPKD progression by altering lipid metabolism-related gene expression.

Key Points: Lack of BMAL1, a circadian clock protein in renal collecting ducts disrupted the clock and increased cyst growth and fibrosis in an ADPKD mouse model.BMAL1 gene deletion increased cell proliferation by increasing lipogenesis in kidney cells.Thus, circadian clock disruption could be a risk factor for accelerated disease progression in patients with ADPKD.