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Sirt1 nutrient signaling regulates fetal programming of nephrogenesis (1033.10)
Author(s) -
Magee Thomas,
Nast Cynthia,
Ross Michael,
Desai Mina
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1033.10
Subject(s) - resveratrol , endocrinology , biology , medicine , fetus , immunohistochemistry , agonist , antagonist , sirtuin 1 , andrology , downregulation and upregulation , receptor , pregnancy , biochemistry , gene , genetics
OBJECTIVE Fetal programming as a result of maternal undernourishment (MUN) results in adult nephropenia and hypertension. In this study we examined the expression of the nutrient sensor SIRT1 and its possible regulation of nephrogenesis. METHODS Pregnant Sprague‐Dawley rat dams were fed either ad libitum diet (control) or were 50% maternal food restricted (MUN) from E10. Fetal kidneys (E20, n=5 dams for MUN and control) were examined for mRNA, protein expression, immunohistochemistry, and epigenetic histone modification at the SIRT1 promoter. To assay the regulation of SIRT1 on nephrogenesis, E16 control rat kidneys (n=10 per group) were incubated ex vivo with the SIRT1 agonist resveratrol or antagonist EX527. Kidneys were fixed and stained with fluorescein‐labeled dolicus bifluoros agglutin, imaged, and terminal buds quantitated. All values are given as mean +/‐ SEM. Data were considered statistically significant by t‐test at p < 0.05. RESULTS Both SIRT1 mRNA (1.6 fold; p < 0.05) and protein expression (1.7 fold; p < 0.05) were increased in MUN kidneys compared to controls. Immunohistochemistry detected SIRT1 expression in MUN and control kidneys. SIRT1 promoter histone H3K9 methylation was reduced by MUN. Control E16 kidneys treated with SIRT1 agonist resveratrol had reduced bud tip number of 23%; p < 0.01; in contrast, treatment with SIRT1 antagonist EX527 increased bud tip number by 57%; p < 0.01. CONCLUSIONS Up‐regulation of SIRT1 during MUN nephrogenesis decreases the number of ureteric bud tips and hence ureteric bud branching rate, thus providing a mechanism for the reduction in nephron number seen during fetal programming. SIRT1 increased activity may be due to reduced histone methylation at the SIRT1 promoter. Grant Funding Source : Supported by NIH grant R03 HD060782‐02 to TRM; NIH AXIS Grant G0811K15 to TRM