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Global analysis of kidney gene expression by RNA-Seq of aged CTRP1-deficient mice

ABSTRACT: Aging affects multi-organ systems. What local and systemic factors influence renal structure and function in aging are not well understood. We and others have shown that the secretory protein, C1q/TNF-related protein 1 (CTRP1), regulates systemic metabolism and cardiovascular function. Whether CTRP1 has a role in kidney function is unknown. We provide evidence here that CTRP1 modulates renal physiology in an age- and sex-dependent manner. In addition to adipose tissue, CTRP1 is also expressed in kidney glomeruli, with podocyte being a major cell source. In mice lacking CTRP1, we observed significant increase in kidney weight and glomeruli hypertrophy in aged (~1 year) male, but not female or younger mice. Although glomerular filtration rate, plasma renin and aldosterone levels, and renal response to water restriction are not different between genotypes, aged CTRP1-deficient male mice have elevated blood pressure. Echocardiogram and pulse wave velocity measurements indicate normal heart function and vascular stiffness in CTRP1 knockout animals. Increased blood pressure is not due to greater salt retention. Paradoxically, CTRP1-deficient mice have elevated urinary sodium and potassium excretion, resulting, in part, from reduced expression of genes involved in renal sodium and potassium reabsorption. Despite renal hypertrophy, gene expression related to inflammation, fibrosis, and oxidative stress are significantly lower in CTRP1-deficient mice. RNA sequencing and pathway analyses reveal additional alterations and enrichments of genes in metabolic processes in the kidney of CTRP1-null animals. These results highlight novel contributions of CTRP1 to aging-associated changes in renal structure and function

ORGANISM(S): Mus musculus

PROVIDER: GSE127332 | GEO | 2020/12/22

REPOSITORIES: GEO

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Project description:Recent evidence suggest that the circadian timing system plays an important role in the control of renal function and maintaining blood pressure. Here, we analyzed circadian rhythms of urinary excretion of sodium and potassium in wild-type mice and mice lacking circadian transcriptional activator clock. Analysis of urines collected at hourly intervals over a 24-hour period revealed dramatic changes in rhythms of sodium and potassium excretion in clock(-/-) mice. In parallel, significant differences in circadian pattern of plasma aldosterone levels, but not in the 24-hour mean aldosterone levels, were observed. Microarray-based profiling of renal transcriptomes demonstrated that clock(-/-) mice exhibit dysregulation in multiple mechanisms involved in maintaining sodium and potassium balance by the kidney. The most significant changes were detected in the expression levels of several key enzymes (Cyp4a14, Cyp4a12a and Cyp4a12b) required for the conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a powerful regulator of renal sodium and potassium excretion, renal vascular tone and blood pressure. The 20-HETE levels measured in kidney microsomes of wild-type mice followed a circadian-like temporal pattern. In clock(-/-) mice, the acrophase of this rhythm was shifted by 8 hours and the 24-hour mean levels of 20-HETE were significantly decreased. These results demonstrate that circadian rhythms of urine electrolyte excretion are largely dependent on the circadian clock activity and indicate that circadian oscillations in renal 20-HETE content could be an important mechanism of blood pressure regulation. We examined the temporal profiles of gene expression in mouse whole kidney. Animals were sacrificed for microdissection every 4 hours, i.e. at ZT0, ZT4, ZT8, ZT12, ZT16 and ZT20 (ZT M-bM-^@M-^S Zeitgeber (circadian) time, indicates time of light-on as ZT0 and time of light-off as ZT12). The microarray hybridization was performed in duplicates on pools of RNA composed of equivalent amounts of RNA prepared from teo or three animals at each ZT time-point.

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Global analysis of kidney gene expression by RNA-Seq of aged CTRP1-deficient mice

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