The effect of sex, growth hormone, and neuropeptide Y on early diabetic kidney disease in adult rats
Description
Thesis (Ph.D.)--Georgetown University, 2008.; Includes bibliographical references. This thesis reports on potential new mechanisms that contribute to sex differences in diabetic renal disease, focusing on estrogen (E2), growth hormone (GH) and two peptides implicated in diabetes- neuropeptide Y (NPY) and angiotensin II (Ang II). To develop this work, our hypotheses were that: 1) under normal conditions, E2 inhibits renal angiotensin II (Ang II) type 1 receptors (AT1R), reducing the effects of circulating Ang II; 2) that diabetes results in a loss of E2 mediated protection, 3) that GH exacerbates renal damage in a sex-dependent manner; and 4) that NPY plays a role in diabetic renal disease. In rats, circulating E2 up-regulated renal estrogen receptors (ERalpha), and significantly reduced renal glomerular AT1R activity, supporting our hypothesis that circulating E2 levels, through renal ERalpha, inhibits AT1R activity in the female kidney, which may explain the female "advantage" seen in many pathologic states. Our studies in diabetic rats induced by STZ (with low circulating E2 levels) determined that renal damage progresses at a similar rate in female and male STZ-only rats, suggesting a loss of female protection with the loss of E2. GH significantly exacerbated renal damage only in male, not female diabetic animals; the pathology was associated with significant increases in many known downstream mediators, specifically implicating inflammation. Finally, our findings of elevated circulating NPY only in STZ+GH males, led to studies focused on the NPY system. We hypothesized that NPY exacerbates renal damage through the Y1 receptor, and that Y1R knock-out (Y1KO) mice would be protected from diabetic renal disease. While changes in NPY did not overtly affect diabetic renal damage in rats, diabetic Y1KO+stressed mice had significant increases in renal damage compared to diabetic WT mice; the Y1KO was also associated with a significant increase in renal Y5R gene expression. We hypothesize that deletion of the Y1R results in a compensatory increase in renal Y5R gene expression, and that the subsequent up-regulation may stimulate a pro-inflammatory pathway. In conclusion, these findings implicate the interactions of sex, GH, and NPY in the progression of diabetic renal disease, providing a rationale for potential sex-specific pharmacologic intervention.
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http://hdl.handle.net/10822/553214Date Published
2008Type
Publisher
Georgetown University
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