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The microRNA-processing enzyme dicer maintains juxtaglomerular cells.

ABSTRACT: Juxtaglomerular cells are highly specialized myoepithelioid granulated cells located in the glomerular afferent arterioles. These cells synthesize and release renin, which distinguishes them from other cells. How these cells maintain their identity, restricted localization, and fate is unknown and is fundamental to the control of BP and homeostasis of fluid and electrolytes. Because microRNAs may control cell fate via temporal and spatial gene regulation, we generated mice with a conditional deletion of Dicer, the RNase III endonuclease that produces mature microRNAs in cells of the renin lineage. Deletion of Dicer severely reduced the number of juxtaglomerular cells, decreased expression of the renin genes (Ren1 and Ren2), lowered plasma renin concentration, and decreased BP. As a consequence of the disappearance of renin-producing cells, the kidneys developed striking vascular abnormalities and prominent striped fibrosis. We conclude that microRNAs maintain the renin-producing juxtaglomerular cells and the morphologic integrity and function of the kidney.

SUBMITTER: Sequeira-Lopez ML

PROVIDER: S-EPMC2831866 | biostudies-other | 2010 Mar

REPOSITORIES: biostudies-other

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The microRNA-processing enzyme dicer maintains juxtaglomerular cells.

Sequeira-Lopez Maria Luisa S ML Weatherford Eric T ET Borges Giulianna R GR Monteagudo Maria C MC Pentz Ellen S ES Harfe Brian D BD Carretero Oscar O Sigmund Curt D CD Gomez R Ariel RA

Journal of the American Society of Nephrology : JASN 20100107 3

Juxtaglomerular cells are highly specialized myoepithelioid granulated cells located in the glomerular afferent arterioles. These cells synthesize and release renin, which distinguishes them from other cells. How these cells maintain their identity, restricted localization, and fate is unknown and is fundamental to the control of BP and homeostasis of fluid and electrolytes. Because microRNAs may control cell fate via temporal and spatial gene regulation, we generated mice with a conditional del ...[more]

PMID: 20056748

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Project description:MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression post-transcriptionally. MiRNAs are implicated in various biological processes associated with obesity, including adipocyte differentiation and lipid metabolism. We used a neuronal-specific inhibition of miRNA maturation in adult mice to study the consequences of miRNA loss on obesity development. Camk2a-CreERT2 (Cre+) and floxed Dicer (Dicerlox/lox) mice were crossed to generate tamoxifen-inducible conditional Dicer knockouts (cKO). Vehicle- and/or tamoxifen-injected Cre+;Dicerlox/lox and Cre+;Dicer+/+ served as controls. Four cohorts were used to a) measure body composition, b) follow food intake and body weight dynamics, c) evaluate basal metabolism and effects of food deprivation, and d) assess the brain transcriptome consequences of miRNA loss. cKO mice developed severe obesity and gained 18 g extra weight over the 5 weeks following tamoxifen injection, mainly due to increased fat mass. This phenotype was highly reproducible and observed in all 38 cKO mice recorded and in none of the controls, excluding possible effects of tamoxifen or the non-induced transgene. Development of obesity was concomitant with hyperphagia, increased food efficiency, and decreased activity. Surprisingly, after reaching maximum body weight, obese cKO mice spontaneously started losing weight as rapidly as it was gained. Weight loss was accompanied by lowered O2-consumption and respiratory-exchange ratio. Brain transcriptome analyses in obese mice identified several obesity-related pathways (e.g. leptin, somatostatin, and nemo-like kinase signaling), as well as genes involved in feeding and appetite (e.g. Pmch, Neurotensin) and in metabolism (e.g. Bmp4, Bmp7, Ptger1, Cox7a1). A gene cluster with anti-correlated expression in the cerebral cortex of post-obese compared to obese mice was enriched for synaptic plasticity pathways. While other studies have identified a role for miRNAs in obesity, we here present a unique model that allows for the study of processes involved in reversing obesity. Moreover, our study identified the cortex as a brain area important for body weight homeostasis.

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The microRNA-processing enzyme dicer maintains juxtaglomerular cells.

Publications

The microRNA-processing enzyme dicer maintains juxtaglomerular cells.

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