Mechanisms of Exercise-Mediated Restoration of Renal Dopamine D1 Receptor Function in Aging
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Renal dopamine plays a pivotal role in the maintenance of sodium homeostasis and blood pressure. Dopamine by activating D1 receptors (D1R) and inhibiting sodium transporters, Na, K-ATPase and Na, H exchanger, in renal proximal tubules (RPTs) promotes sodium excretion and thus maintains sodium homeostasis. The aging process alters vital organ functions including kidney function. Our previous studies have demonstrated a diminished natriuretic response to dopamine in aging kidneys. Age-associated oxidative stress is reported to increase D1R serine-phosphorylation via PKC/GRK-2 pathway. This causes D1R G-protein uncoupling and the inability of D1R agonist SKF-38393 to inhibit Na, K-ATPase in RPTs and subsequently promote sodium excretion in old rats. Exercise improves physiological function and reduces mortality. However, it is not known whether exercise reverses the age-related decline in D1R function. Therefore, the objective of this project was to determine if exercise could restore renal D1R function. The first part of the project studied the effect of exercise on natriuretic response to D1R agonist SKF-38393, revealing an increased sodium excretion with SKF-38393 in exercised compared to sedentary aged rats indicating restoration of D1R function. The second part studied the molecular events in RPTs. The study revealed that exercise mediated antioxidant enzymes over-expression, reduction in oxidative stress, decrease in PKC activity and D1R serine-phosphorylation and increase in D1R-G protein coupling and inhibitory effect of SKF-38393 on Na, K-ATPase in aged rats. Also, these events were associated with increased activation of transcription factors NF-κB and Nrf-2 in exercised aged rats. The third part of the project elucidated a causative role of NF-κB and/or Nrf-2 in antioxidant enzymes expression and subsequent protection from oxidative stress-induced D1R dysfunction in NF-κB and/or Nrf-2 transfected HK-2 cells. The study showed that NF-κB and/or Nrf-2 increased antioxidant enzyme levels and ability of SKF-38393 to stimulate 35S-GTPγS binding (index of D1 receptor function) even in the presence of the oxidant H2O2. Taken together, these studies demonstrate that the mechanism of exercise mediated decrease in oxidative stress and restoration of renal D1R function in aging involves exercise-induced increase in antioxidant defense via NF-κB and/or Nrf-2.