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Our overall paradigm-shifting hypothesis is that the circadian clock functions differently in the kidneys of females compared to males. Our recent, unexpected data show that the expression of key clock genes is higher in female vs. male kidneys and the night/day ratio of expression is also greater in female kidneys. These data suggest that females have a more robust circadian clock mechanism within the kidney. The circadian clock is made up of a core group of transcription factors that regulate the expression of several thousand genes in the kidney. Because the circadian clock functions as a master regulator of gene expression in the kidney, we hypothesize that a more robust circadian clock in females may be the mechanism that provides protection from kidney disease and hypertension in premenopausal females. More robust expression of circadian clock target genes related to renal function in females may provide resilience in the face of kidney disease or hypertension. To test this, we must first establish the sex-specific mechanism of the circadian clock in the kidney. Our pioneering approach for this proposal is to perform single cell RNAseq using kidneys collected from males and females every four hours over a 24-hour circadian cycle. This approach will provide the very first sex-specific single cell circadian transcriptomic landscape of the kidney. The work proposed here will launch an entirely new line of research into understanding the kidney circadian clocks and the regulation of renal function as well as provide a powerful resource that will be shared with the entire renal physiology community. If the clock does indeed function differently in female vs. male kidneys, these studies will not only have a tremendous impact on renal physiology but will also have dramatic implications for our overall understanding of circadian biology. If we can identify mechanisms of protection in younger females, that information could be leveraged to develop better therapies for kidney disease and hypertension in men and postmenopausal women.
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