In this proposal renal and urinary tract changes associated with pregnancy, the post-partum period, and alterations in estrogen and progesterone levels will be defined. These changes will be examined from the physiologic to the cellular and ultrastructural level using physiologic rat models, novel magnetic resonance imaging techniques, and histologic morphometric and molecular analysis. 1) Specific Aim 1: To extend previous studies showing that urinary tract dilation during pregnancy is caused by increased urinary tract smooth muscle compliance and not obstruction and confirm that these renal and urinary tract changes are accompanied by increased blood and tissue flow. A rat model will be used to measure continuous renal pelvic and bladder pressures with varying urinary flow rates and bladder volumes in pregnant, nonpregnant, post-parturition, and estrogen and progesterone treated rats. Using ultrafast contrast enhanced magnetic resonance imaging (MRI) techniques that were previously developed for this rat model we will assess renal and urinary tract morphology, global and regional blood flow, and renal functional changes for these conditions. Relative renal artery flow rates obtained in the physiologic studies will be correlated with those obtained by MRI studies. 2) Specific Aim 2: To examine smooth muscle contractility in the rabbit bladder during and after pregnancy and with estrogen and progesterone manipulation. Preliminary studies have shown that estrogen administration increases rabbit bladder mass and adrenergic and cholinergic sensitivity. Bladder dome, urethral, and aortic tissues will be studied for contractility to different adrenergic and cholinergic drugs to demonstrate changes with pregnancy and estrogen and progesterone manipulation. 3) Specific Aim 3: To examine whether pregnancy, estrogen, and progesterone cause changes in collagen architecture and distribution in the kidney and bladder and whether such changes return to baseline after parturition. The kidneys and urinary tract of animals from specific aims l and 2 will be examined qualitatively and quantitatively for collagen distribution to relate physiologic changes to changes in collagen architecture or distribution. Tissue sections will be examined for ultrastructural changes and then for volumetric and distribution changes of collagen and smooth muscle using morphometric analysis. Tissue extraction of collagen with electrophoretic separation will allow ratios of various collagen types to be determined and correlated with known rapid changes in collagen content in other organs. 4) Specific Aim 4: To describe the pathogenesis of pyelonephritis during pregnancy and determine whether the infected urinary tract undergoes physiologic changes during pregnancy that result in increased likelihood of pyelonephritis. The pathogenesis of bacteriuria in pregnant and nonpregnant rats will be compared physiologically and with MRI. The use of MRI as a primary tool for evaluating of urinary infection will be assessed. Better understanding of pregnancy, and estrogen and progesterone-related effects on the urinary tract could offer new means of evaluating and managing 1) the dilated fetal urinary tract that is exposed to maternal estrogen and progesterone, 2) pregnancy related diseases such as increased pyelonephritis, and 3) age related changes such as incontinence and bladder irritability.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (SRC (07))
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Stanford University
Schools of Medicine
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Shortliffe, Linda M Dairiki; Ye, Youxin; Behr, Barry et al. (2014) Testosterone changes bladder and kidney structure in juvenile male rats. J Urol 191:1913-9
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Rodriguez, Larissa V; Wang, Bingyin; Shortliffe, Linda M D (2004) Structural changes in the bladder walls of pregnant and hormone-treated rats: correlation with bladder dynamics. BJU Int 94:1366-72
Hansen, Moritz H; Wang, Bing-Yin; Afzal, Naveed et al. (2003) Effect of urinary tract infection on ureteropelvic junction obstruction in a rat model. Urology 61:858-63