The renin-angiotensin system and the lower urinary tract in diabetes
Nearly 8% of the US population has diabetes, with an additional 26% of adults over 20 likely to develop diabetes. Urological complications develop in up to 80% of diabetics, the most common being lower urinary tract (LUT) dysfunction. This is a long-term problem, with changes over time from LUT hyperactivity to hypoactivity, and seriously compromises the quality of life in diabetics. Overactivity of the renin-angiotensin system (RAS) is an important component of diabetes. Its principal product angiotensin II is known to affect the LUT, and it is known that diabetes itself as well as treatments to reduce angiotensin II or block its binding to AT1 receptors produce marked changes in the proportions of AT1 and AT2 receptors which promote contraction and relaxation of smooth muscle, respectively. Nonetheless, we know next to nothing about RAS overactivity and LUT function in diabetes. Consequently, we do not know how RAS overactivity or treatments to reduce it affect diabetic LUT function, nor how modulation of RAS activity could be harnessed to improve diabetic LUT function. Our overarching hypothesis is that RAS overactivity in the setting of diabetes contributes to LUT dysfunction in a time-dependent manner; moreover, treatment of hypertension and nephropathy in diabetic patients by the inhibition of RAS overactivity may further contribute to LUT dysfunction. To explore this hypothesis, we will study mice after 6 or 14 wk of hyperglycemia and with or without chronic angiotensin II treatment. Our associated specific aims are: Specific aim 1. Using cystometry and leak-point pressure methodology, determine the effects of chronic angiotensin II treatment on the LUTs of 129/SvEv mice with and without Akita diabetes. Specific aim 2. Using isolated preparations from the bladder and urethra in vitro, determine the effects of acute and chronic angiotensin II treatment on LUT contractility in mice with and without Akita diabetes and show the functional dependence on AT1 vs AT2 receptors. Specific aim 3. Using fixed LUTs, use histologic and immunohistochemical methods to determine the effects of diabetes and chronic angiotensin II treatment on the expression and distribution of angiotensin II and its AT1 and AT2 receptors and on the smooth muscle and collagen of the LUT.

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