Circadian Clock Disruption and Growth of Kidney Cysts in Autosomal Dominant Polycystic Kidney Disease.

Abstract

Lack of <i>Bmal1</i>, a circadian clock protein in renal collecting ducts disrupted the clock and increased cyst growth and fibrosis in an autosomal dominant polycystic kidney disease mouse model. <i>Bmal1</i> 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 autosomal dominant polycystic kidney disease. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the <i>PKD1</i> and <i>PKD2</i> genes and often progresses to kidney failure. ADPKD progression is not uniform among patients, suggesting that factors secondary to the <i>PKD1/2</i> 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. To disrupt the circadian clock, we deleted <i>Bmal1</i> gene in the renal collecting ducts of the <i>Pkd1</i>^RC/RC (RC/RC) mouse model of ADPKD (RC/RC;<i>Bmal1</i>^f/f;<i>Pkhd1</i>^cre, called double knockout [DKO] mice) and in <i>Pkd1</i> knockout mouse inner medullary collecting duct cells (<i>Pkd1Bmal1</i>KO mouse renal inner medullary collecting duct cells). Only male mice were used. Human nephrectomy ADPKD kidneys showed altered clock gene expression when compared with normal control human kidneys. When compared with 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 with RC/RC kidneys. Similarly, <i>in vitro</i>, <i>Pkd1Bmal1</i>KO cells showed altered clock genes, increased lipogenesis and cholesterol synthesis–related genes, and reduced fatty acid oxidation–related gene expression compared with <i>Pkd1KO</i> cells. The <i>Pkd1Bmal1</i>KO cells showed increased cell proliferation compared with <i>Pkd1KO</i> cells, which was rescued by pharmacological inhibition of lipogenesis. Renal collecting duct–specific <i>Bmal1</i> gene deletion disrupted the circadian clock and triggered accelerated ADPKD progression by altering lipid metabolism–related gene expression.