Sex-specific effects of low protein diet on in utero programming of renal G-protein coupled receptors.
Intrauterine growth restriction (IUGR) is an important risk factor for development of hypertension, diabetes and the metabolic syndrome. Maternal low protein (LP) intake during rat pregnancy leads to IUGR in male and female offspring, although females may be resistant to the development of effect. Current evidence suggests that changes in the renin-angiotensin system (RAS) in utero contribute to this programmed hypertension, via sex-specific mechanisms. The previously orphaned G-protein coupled receptor (GPR91) was identified as a central player in the development of hypertension in adult mice, through a RAS-dependent pathway. However, whether the GPR91 pathway contributes to fetal programming is unknown. Furthermore, the nature of involvement of downstream modulators of the RAS including Gqα/11α and GαS has not been investigated in IUGR-LP rats. Therefore, we postulated that renal GPR91, in conjunction with RAS, is differentially impacted in a sex-specific manner from LP-induced IUGR rats. Pregnant Wistar rats were fed control (C, 20% protein) or LP (8% protein) diet until embryonic day 19 (E19) or postnatal d21. At E19, GPR91 protein and mRNA were increased in both male and female LP kidneys (P<0.05), whereas renin and angiotensin converting enzyme (ACE) were only increased in males (P=0.06 and P<0.05, respectively). On d21, AT1R and Gqα/11α were increased in LP males, while in LP females, AT2R protein was elevated and renin expression was decreased (P<0.05). This study demonstrates that in IUGR-LP rats, up regulation of GPR91 in fetal kidney is mirrored by increased ACE and renin in males. These in utero alterations, when combined with postnatal increases in AT1R-Gqα/11α specifically in male offspring, may predispose to the development of hypertension.
1 Department of Obstetrics and Gynecology, Lawson Research Institute, Western University, London, ON, Canada.
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Cooke
1 Department of Obstetrics and Gynecology, Lawson Research Institute, Western University, London, ON, Canada.
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Zhao
2 Department of Physiology and Pharmacology, Lawson Research Institute, Western University, London, ON, Canada.
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Gysler
3 Department of Medicine, Lawson Research Institute, Western University, London, ON, Canada.
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Arany
1 Department of Obstetrics and Gynecology, Lawson Research Institute, Western University, London, ON, Canada.
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Regnault
D000818:Animals; D018753:Diet, Protein-Restricted / Q000009:adverse effects*; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D011247:Pregnancy; D039401:Prenatal Nutritional Physiological Phenomena; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism / Q000502:physiology; D012737:Sex Factors
D043562:Receptors, G-Protein-Coupled; C523503:Sucnr1 protein, rat