PATHOPHYSIOLOGY OF THE AGING KIDNEY

Summary

Principal Investigator: S Anderson
Abstract: DESCRIPTION: Glomerular hemodynamic changes and angiotensin II (Ang II) participate in the age-related changes in renal function. Aging rats develop glomerular capillary hypertension, and blockade of Ang 11 slows age-related nephropathy. However, renal responsiveness to Ang 11 blockade declines in the course of aging. Three complementary hypotheses are proposed: First, the renal renin-angiotensin system (RAS) may be considered as two distinct systems: a vascular system (composing the plasma and vasculature, including glomeruli), and a tubulointerstitial system. Second, these two systems change with aging, not necessarily in coordinated fashion with maladaptive RAS changes contributing to age-related injury. Third, in aging there is a shift in the balance between constrictor and vasodilatory mediators, so that the former predominate. In support of these hypotheses, the applicant has found that plasma Ang II levels fall, but that renal Ang II levels (presumably tubulointerstitial) are high in the aging rat. Furthermore, aging rats exhibit greater renal responses to vasoconstrictors, but not to vasodilator stimuli. Thus, a predominance of Ang II (and other vasoconstrictors) may be a heretofore unrecognized key participant in the pathogenesis of age-related renal injury. Perturbations in the balance affect hemodynamics, but also lead to changes in effectors which are regulated by those mediators. There are three specific aims. (1) To localize and quantify the anomalies of the vascular and tubulointerstitial renin angiotensin systems in aging, by determining the site(s) of discordant RAS component processing; (2) to evaluate the mechanisms by which long-term angiotensin converting enzyme (ACE) inhibition protects against chronic age-related injury, by comparison with other antihypertensive regimens, and by evaluating effects of therapy on hemodynamic function and mediators of injury; and (3) to examine the activity of the renal dopaminergic system, and its interactions with the RAS, in regulation of hemodynamic and natriuretic function in the aging kidney. The use of a combined physiological, biochemical, immunohistochemical, and molecular biologic approach should gain insight into this clinically important but understudied problem.
Funding Period: 1997-09-30 - 2003-08-31
more information: NIH RePORT

Top Publications

  1. pmc The aging kidney: physiological changes
    Jessica R Weinstein
    Oregon Health and Science University, Portland, 97239, USA
    Adv Chronic Kidney Dis 17:302-7. 2010
  2. ncbi EphA2: expression in the renal medulla and regulation by hypertonicity and urea stress in vitro and in vivo
    Hongshi Xu
    Mailcode PP262, Oregon Health and Science Univ, 3314 S W US Veterans Hospital Rd, Portland, OR 97201, USA
    Am J Physiol Renal Physiol 288:F855-66. 2005
  3. ncbi Cyclo-oxygenase-2 inhibition attenuates the progression of nephropathy in uninephrectomized diabetic rats
    Radko Komers
    Division of Nephrology and Hypertension, Oregon Health and Science University, Potland, Oregon 97239 2940, USA
    Clin Exp Pharmacol Physiol 34:36-41. 2007

Scientific Experts

  • R Komers
  • Jessica R Weinstein
  • Sharon Anderson
  • Hongshi Xu
  • Wei Tian
  • Jessie N Lindsley
  • Christopher J Rivard
  • Terry T Oyama
  • Herbert T Cohen
  • David M Cohen
  • Serena M Bagnasco
  • Juan M Capasso

Detail Information

Publications3

  1. pmc The aging kidney: physiological changes
    Jessica R Weinstein
    Oregon Health and Science University, Portland, 97239, USA
    Adv Chronic Kidney Dis 17:302-7. 2010
    ..These changes may predispose the older kidney to acute kidney injury, including normotensive ischemic nephropathy, as well as progressive chronic kidney disease...
  2. ncbi EphA2: expression in the renal medulla and regulation by hypertonicity and urea stress in vitro and in vivo
    Hongshi Xu
    Mailcode PP262, Oregon Health and Science Univ, 3314 S W US Veterans Hospital Rd, Portland, OR 97201, USA
    Am J Physiol Renal Physiol 288:F855-66. 2005
    ..Renal medullary EphA2 expression may represent an adaptive response to medullary hypertonicity or urea exposure...
  3. ncbi Cyclo-oxygenase-2 inhibition attenuates the progression of nephropathy in uninephrectomized diabetic rats
    Radko Komers
    Division of Nephrology and Hypertension, Oregon Health and Science University, Potland, Oregon 97239 2940, USA
    Clin Exp Pharmacol Physiol 34:36-41. 2007
    ..4. In conclusion, long-term COX-2 inhibition is associated with modest nephroprotection in uninephrectomized diabetic rats when administered as late intervention. These effects are independent of metabolic control and blood pressure...