Pkd1 Deficiency Causes Intrinsic Renal Circadian Clock Dysfunction.

BACKGROUND

Circadian rhythms are governed by cell-autonomous molecular clocks that regulate organ function and homeostasis. We previously showed that disruption of the renal circadian clock accelerates cyst growth in a mouse model of autosomal dominant polycystic kidney disease (ADPKD). Whether ADPKD is associated with intrinsic renal circadian clock dysfunction, and whether such dysfunction is directly attributable to loss of the PKD1 gene, remain unknown.

METHODS

We examined circadian regulation across organismal, organ and cellular levels using slow (Pkd1RC/RC) and rapidly (Pkd1-KO) progressing ADPKD mouse models, along with Pkd1 deficient proximal tubular and inner medullary collecting duct cells. Diurnal water intake and urine output were assessed longitudinally. Time-course analyses of core clock gene expression in mouse kidneys and synchronized renal epithelial cells, together with real-time Per2luciferase (PER2::LUC) bioluminescence imaging of kidney explants, were performed.

RESULTS

Pkd1RC/RC mice showed progressive disruption of diurnal rhythms in water intake and urine output, paralleling cystic burden. Cystic kidneys exhibited dampened, desynchronized oscillations of core circadian clock genes and PER2::LUC bioluminescence. These abnormalities were more pronounced in Pkd1-KO mice. Furthermore, Pkd1 loss blunted clock gene oscillations in synchronized renal epithelial cells in vitro, indicating cell-autonomous circadian clock dysfunction.

CONCLUSIONS

Pkd1 deficiency contributes to intrinsic renal circadian clock dysfunction independent of systemic cues, although additional studies will be required to distinguish direct effects of Pkd1 loss from secondary consequences of cystic remodeling in vivo.