Key Points

Lack of Bmal1, 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.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 autosomal dominant polycystic kidney disease.

Background

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the PKD1 and PKD2 genes and often progresses to kidney failure. ADPKD progression is not uniform among patients, suggesting that factors secondary to the PKD1/2 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 Bmal1 gene in the renal collecting ducts of the Pkd1RC/RC (RC/RC) mouse model of ADPKD (RC/RC;Bmal1f/f;Pkhd1cre, called double knockout [DKO] mice) and in Pkd1 knockout mouse inner medullary collecting duct cells (Pkd1Bmal1KO mouse renal inner medullary collecting duct cells). Only male mice were used.

Results

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, in vitro, Pkd1Bmal1KO cells showed altered clock genes, increased lipogenesis and cholesterol synthesis–related genes, and reduced fatty acid oxidation–related gene expression compared with Pkd1KO cells. The Pkd1Bmal1KO cells showed increased cell proliferation compared with Pkd1KO cells, which was rescued by pharmacological inhibition of lipogenesis.

Conclusions

Renal collecting duct–specific Bmal1 gene deletion disrupted the circadian clock and triggered accelerated ADPKD progression by altering lipid metabolism–related gene expression.