Circadian clock gene BMAL1 reduces urinary calcium oxalate stones formation by regulating NRF2/HO-1 pathway.

ABSTRACT

Calcium oxalate stones are closely related to oxalate metabolism and oxidative stress injury. Normal metabolism homeostasis and tissue repair are often affected by the biological rhythm, which plays an indispensable role in maintaining the homeostasis of the organism. Nuclear factor erythroid 2-related factor/heme oxygenase-1 (NRF2/HO-1) is one pathway related to oxidative stress injury in human body. Normal operation of this pathway is conducive to the resistance against oxidative stress-related injury. This study was mainly aimed to explore whether the rhythm gene "brain and muscle ARNT-like 1" (BMAL1) was involved in regulating oxidative stress-related NRF2/HO-1 pathway to reduce the formation of urinary calcium oxalate stones. In vitro experiment found that the activation of NRF2/HO-1 can significantly reduce the oxalate-induced oxidative damage and urinary calcium oxalate stone formation, and the relative expression of BMAL1 was increased. Then overexpression of circadian gene BMAL1 can activate the NRF2/HO-1 pathway and reduce the oxalate-induced oxidative damage. In the hyperoxaluria animal model, the BMAL1 expression level decreased obviously, and the production of calcium oxalate stones was significantly reduced after activating NRF2/HO-1. Finally, we further verified the BMAL1 expression in blood samples from the patients, and analysis of several single nucleotide polymorphisms showed BMAL1 was related to calcium oxalate stones. Therefore, maintaining normal biorhythms and appropriately intervening related rhythm genes and their downstream antioxidant pathways may play an important role in the prevention and postoperative recurrence of urinary calcium oxalate calculi, which may open up new directions for the treatment of urinary calculi.