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Factors Regulating the Intrarenal Renin-Angiotensin System and Renal Damage During Aging

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Factors Regulating the Intrarenal Renin-Angiotensin System and Renal Damage During Aging
Gilliam-Davis, Shea
The renin-angiotensin system (RAS) plays an important role in regulating blood pressure, fluid homeostasis, and it even contributes to insulin resistance. Dysfunction of this system ultimately leads to cardiovascular related diseases, such as hypertension and diabetes. Studies show that RAS blockade reduces the onset of the metabolic syndrome (MetS) and type 2 diabetes, however, the precise mechanisms underlying the beneficial effects are not entirely known. The activation of the intrarenal RAS and onset of renal dysfunction occurs over the same time span as many of the features of the MetS, while the systemic RAS declines. This suggests that suppression of the intrarenal RAS may be partly responsible for the salutary effects of RAS blockade. However, the exact timing and mechanisms underlying the increase in the intrarenal RAS are not entirely known. We used Fischer 344 (F344) and Sprague Dawley (SD) rats because both strains develop insulin resistance and kidney damage (proteinuria) during aging with the SD rats also developing an increase in blood pressure. Long-term (1 year) systemic RAS blockade with the angiotensin (Ang) II type 1 (AT1) receptor antagonist L-158,809 in the F344 rats prevented the age-related increase in serum leptin, insulin, glucose, body weight and increased excretion of Ang peptides and protein that occur independently of blood pressure or plasma RAS peptides. F344 rats also have increased gene expression of brain (dorsomedial medulla) angiotensinogen with a similar trend for renin, while the expression of ACE2 and neprilysin remain the same with a decrease in ACE expression compared to younger animals. There was no change in the gene expression of AT1a, AT1b, AT2 or Mas receptors in the dorsomedial medulla during aging in the F344 rats but there was a decrease in leptin receptor expression and an increase in the expression of the PI3K p85 regulatory subunit. L-158,809 increased angiotensinogen, ACE, ACE2 and neprilysin mRNA with a similar trend for renin. RAS blockade also increased AT1b, AT2, Mas and leptin receptor mRNA as well as the p85 subunit expression. Thus, insulin resistance, renal injury and activation of the intrarenal RAS during early aging in normotensive animals can be prevented by systemic RAS blockade in association with changes in dorsomedial medulla enzymes and receptors that would shift the balance from Ang II to Ang-(1-7) in this brain region. The prevention of age-related declines in the leptin receptor and enhancement of a leptin signaling pathway provides mechanisms for preservation of metabolic function in treated F344 rats. To better define the time course of intrarenal RAS activation relative to the elevation in proteinuria in aging SD rats and to provide information on possible mechanisms underlying intrarenal RAS activation, the intrarenal RAS, proteinuria as well as indices of metabolism were studied from 24 to 48 wks of age. In addition, bilateral renal denervations were performed at 28 weeks or 75 weeks of age in SD rats. SD rats have a significant increase in the excretion of Ang I, Ang-(1-7), and protein, but not Ang II at 38 wks of age with an increase in urinary creatinine at 27 wks of age. Bilateral renal denervation in 28 week old SD rats significantly lowered blood pressure for at least five weeks post-surgery without altering Ang peptides or creatinine excretion. Protein excretion increased in control animals and this was prevented or delayed in denervated rats. Bilateral renal denervation in 75 week old SD rats significantly lowered blood pressure for one week post-surgery without changing protein, creatinine or Ang peptides excretion. Renal nerves appear to contribute to renal damage (proteinuria) independent of changes in Ang II excretion but only during the early stages of aging. Renal nerves do not contribute to long-term support of blood pressure in older rats with existing renal impairment. Renal denervation is not sufficient to reverse or prevent continuing declines in renal function (increases in urinary Ang II or protein) at this late time point. Based on these studies, we suggests that the intrarenal, systemic and brain RAS are independently regulated during aging, each may contribute to age-related metabolic derangements and renal damage independently of pressure, and that renal nerves may play a role in initiation of the renal damage but not regulation of the intrarenal RAS.
Renin-Angiotensin System
Renal Damage
Robbins, Michael (committee chair)
Diz, Debra (committee member)
Chappell, Mark (committee member)
Strandhoy, Jack (committee member)
Groban, Leanne (committee member)
2009-05-14T15:42:49Z (accessioned)
2010-06-18T18:57:38Z (accessioned)
2009-05-14T15:42:49Z (available)
2010-06-18T18:57:38Z (available)
2009-05-14T15:42:49Z (issued)
Physiology (discipline)
http://hdl.handle.net/10339/14706 (uri)
en_US (iso)
Wake Forest University
Release the entire work for access only to the Wake Forest University system for one year from the date below. After one year, release the entire work for access worldwide. (accessRights)

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