Knockout of circadian protein Period1 (Per1) and time of day alter the renal transcriptomic profile of Dahl SS rats
Authors: Dissanayake Lashodya , Zietara Adrian , Gumz Michelle , Staruschenko Alexander 
Published: May 2023

Circadian rhythm in the body is regulated through a central clock in the brain signaling through molecular clocks in the peripheral tissue. PER1, CRY, CLOCK, and BMAL1 are the 4 genes regulating the mechanism of the molecular clock. It has been established that the function and gene expression in the kidney has endogenous rhythms that are dependent upon the time of the day, yet most studies have focused on extrarenal tissue. Our recent study showed that a global knockout of Per1 in the Dahl salt-sensitive (SS) background exacerbated hypertension and kidney damage and led to a desynchrony of BP rhythms.To further dissect the effect of knocking out PER1 and find possible gene expression pattern differences based on the time of day, we performed transcriptomics analyses of kidney cortex tissue from SS and SSPer1-/- rats when rats were fed a high salt diet. The tissue was collected at two time points, one in the active night cycle and the other during the inactive day cycle (N=5 per group). The number of significantly differentially expressed identifiable genes (-1> log2 fold change >1, adjusted P value < 0.05) for each of the comparisons is as follows: Day SSPer1-/- vs SS – 610; Night SSPer1-/- vs SS – 355; SSPer1-/- Night vs SSPer1-/- Day – 60; SS Night vs SS Day – 120. Interestingly, the expression of Bmal1 was decreased in SSPer1-/- rats during the night compared to SS rats but increased compared to SSPer1-/- collected during the day. Clock, Cry2, and Per2 expression in the kidney were affected by time of day but not by genotype. Edn1 expression, which has previously been shown to be regulated by PER1 in mice, was affected by genotype but not by time of day.All differentially expressed genes were further analyzed using Ingenuity Pathway Analysis (IPA, QIAGEN). The results from the daytime collections were examined to get insights into the phenotype reported previously in SSPer1-/-. Circadian rhythm signaling, endothelin-1 signaling, and MYC-mediated apoptosis signaling (-log(p-value) 2.58, 2.8, & 3.24) were predicted to be enhanced in the overlapping canonical pathways. Renal damage (z score 4.51E-10) was predicted to be upregulated in SSPer1-/- rats with the influence of significantly increased expression of genes such as Timp1, Hmox1, and Edn1. The most inhibited bio function was the transport of molecules. Interleukin-1β and aldosterone, which have been previously shown to be under the regulation of clock genes, were among the suggested upstream regulators (z score 2.17 & 2.05).Our study showed that loss of PER1 affects the gene expression patterns in the kidney, highlighting pathways and genes related to hypertension, circadian rhythm, and kidney damage that will influence future studies. Functional studies are necessary to confirm the predictions made through transcriptomic data.

This research was supported by National Institutes of Health grants R35 HL135749 (to AS).

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.