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Although the gonads have long been assumed to be the primary source of bioactive sex hormones, evidence suggests that sex hormones can be produced extragonadally. Our overall paradigm-shifting hypothesis is that the kidney has an intrinsic capacity to biosynthesize estrogen and this intrarenal steroidogenic capacity is enhanced in the female, relative to the male, kidney. Our recent unexpected RNA sequencing data indicate that the estrogen biosynthesis pathway is activated in the renal inner medulla of female Sprague Dawley (SD) rats compared with that of males. In addition, we found that renal inner medullary expression of the gene encoding aromatase (estrogen synthase), the key enzyme in estrogen biosynthesis pathway, is increased in response to a high salt diet in female, but not male, SD rats. This data suggest that female kidney locally biosynthesize estradiol (E2) to promote natriuresis and maintain blood pressure. Because activation of renal medullary G protein coupled estrogen receptor 1 (GPER1) promotes natriuresis and protect against hypertension and kidney disease in females, we hypothesize that a more robust intrarenal machinery to biosynthesize E2 provides protection to premenopausal females against hypertension and kidney disease. The proposed studies require bridging multiple disciplines and scientific advances in nephrology, endocrinology, cardiovascular disease, microscopy, and radiology. We will employ surgical approaches (chronic renal medullary infusion using iPRECIO innovative drug infusion technology) and novel applications for an established technique (radiotracer study using renal imaging by [11C]cetrozole positron emission tomography) to allow us to unravel sex-differences in the potential of the kidney to biosynthesize E2. A successful outcome of the current study would justify the future development of therapeutics that increase intrarenal E2 biosynthesis to protect against hypertension This study will challenge a central paradigm in renal physiology that considers the kidney to be a non-steroidogenic organ and create a new field of research focusing on understanding the kidney from an endocrine point of view: “Renal Endocrinology”. Establishment of the kidney as a site for extragonadal E2 biosynthesis will be transformational for nephrology and hypertension research.
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