Exercise decreases oxidative stress and inflammation and restores renal dopamine D1 receptor function in old rats

2007 ◽  
Vol 293 (3) ◽  
pp. F914-F919 ◽  
Author(s):  
Mohammad Asghar ◽  
Liza George ◽  
Mustafa F. Lokhandwala
Keyword(s):  
Oxidative Stress ◽  
G Protein ◽  
Sch 23390 ◽  
D1 Receptor ◽  
Skf 38393 ◽  
Receptor Function ◽  
Protein Activation ◽  
G Protein Activation ◽  
Anti Oxidant ◽  
Old Rats

Recently, we reported that oxidative stress decreases D1 receptor numbers and G protein activation in renal proximal tubules (RPT), resulting in diminished natriuretic response to dopamine in old rats. We tested the hypothesis that exercise in old rats will decrease oxidative stress and restore natriuretic response to D1 receptor agonist, SKF 38393. Old (23 mo) rats were subjected to rest (sedentary) or to treadmill exercise followed by measurement of oxidative stress [malondialdehyde (MDA)], inflammation [C-reactive protein (CRP)], anti-inflammation (IL-10), antioxidant enzyme [superoxide dismutase (SOD)], and natriuretic response to SKF 38393. We found that MDA levels decreased and total SOD activity and Cu/ZnSOD protein increased in RPT of exercised rats. Exercise increased the nuclear levels of Nrf2 transcription factor (which binds to anti-oxidant response elements) in RPT. The levels of CRP decreased and IL-10 increased in RPT of exercised rats. Furthermore, exercise increased the basal bindings of [3H]SCH 23390 and [35S]GTPγS (indexes of D1 receptor number and G protein activation, respectively) together with D1 receptor and Gαq proteins in RPT membranes. Moreover, SKF 38393 increased sodium excretion in exercised rats. Also, exercise decreased the levels of proteins in the urine of old rats. These results demonstrate that exercise decreases oxidative stress, inflammation, and proteinuria and increases anti-oxidant defense and D1 receptor function in old rats. Therefore, exercise may prove beneficial in preventing age-associated increases in oxidative stress, inflammation, and preserving kidney function, in general, and renal D1 receptor responsiveness, in particular.

Alterations in dopamine DA1 receptor and G proteins in renal proximal tubules of old rats

1997 ◽  
Vol 273 (1) ◽  
pp. F53-F59 ◽  
Author(s):  
V. Kansra ◽  
T. Hussain ◽  
M. F. Lokhandwala
Keyword(s):  
Atpase Activity ◽  
G Proteins ◽  
Sch 23390 ◽  
Skf 38393 ◽  
Proximal Tubules ◽  
Adult Rats ◽  
Protein Activation ◽  
Proximal Tubular ◽  
Old Rats ◽  
Renal Proximal Tubular

The present study examines the effect of dopamine DA1-receptor agonists on the renal proximal tubular Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) activity and quantitates DA1 receptors and the coupled G proteins in Fischer 344 model of adult (6 mo old) and old (23 mo old) rats. Dopamine and the preferential DA1-receptor agonist, SKF-38393, produced a concentration-dependent inhibition of Na(+)-K(+)-ATPase activity in proximal tubules from adult rats, whereas the enzyme activity was unaffected by these agonists in the old rats. The binding of DA1-receptor antagonist [3H]Sch-23390 in the proximal tubular basolateral membranes showed a marked decrease (approximately 47%) in the receptor numbers in old compared with adult rats, whereas dissociation constant (Kd) values in old compared with adult rats were not significantly different. Dopamine and SKF-38393 stimulated 35S-labeled guanosine 5'-O-(3-thiotriphosphate) binding in adult rats, but there was no significant effect on the binding in the old rats. Quantification of G2 alpha and Gq/11 alpha using Western analysis revealed a significant increase in quantities of both the G proteins in old rats. The data suggest that a reduction in DA1 receptor number and subsequently reduced G protein activation may be the causative factors for the impairment in DA1 receptor-mediated inhibition of Na(+)-K(+)-ATPase activity in the proximal tubules of old rats.

Role of oxidative stress in defective renal dopamine D1 receptor-G protein coupling and function in old Fischer 344 rats

2006 ◽  
Vol 291 (5) ◽  
pp. F945-F951 ◽  
Author(s):  
Riham Zein Fardoun ◽  
Mohammad Asghar ◽  
Mustafa Lokhandwala
Keyword(s):  
Oxidative Stress ◽  
G Protein ◽  
D1 Receptor ◽  
Serine Phosphorylation ◽  
D1 Receptors ◽  
Adult Rats ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Age Related ◽  
Old Rats

Aging is associated with an increase in oxidative stress. Previously, we have reported that dopamine failed to inhibit proximal tubular Na-K-ATPase and to promote sodium excretion in old rats (Beheray S, Kansra V, Hussain T, and Lokhandwala MF. Kidney Int 58: 712–720, 2000). This was due to uncoupling of dopamine D1 receptors from G proteins resulting from hyperphosphorylation of D1 receptors. The present study was designed to test the role of oxidative stress in the age-related decline in renal dopamine D1 receptor function. We observed that old animals had increased malondialdehyde (MDA) levels, a biomarker of oxidative stress, and decreased D1 receptor number and protein in the proximal tubules (PT) compared with adult rats. In old rats, there was increased G protein-coupled receptor kinase-2 (GRK-2) abundance, increased basal serine phosphorylation of D1 receptors, and defective D1 receptor-G protein coupling in PT membranes. Interestingly, supplementation with an antioxidant, tempol (1 mmol/l in drinking water for 15 days), lowered MDA levels and normalized D1 receptor number and protein in old rats to the level seen in adult rats. Furthermore, tempol decreased GRK-2 abundance and D1 receptor serine phosphorylation and restored D1 receptor-G protein coupling in PT of old rats. The functional consequence of these changes was the restoration of the natriuretic response to D1 receptor activation in tempol-supplemented old rats. Therefore, in old rats, tempol reduces oxidative stress and prevents GRK-2 membranous abundance and hyperphosphorylation of D1 receptors, resulting in restoration of D1 receptor-G protein coupling and the natriuretic response to SKF-38393. Thus tempol, by lowering oxidative stress, normalizes the age-related decline in dopamine receptor function.

scholarly journals Renal proximal tubules from old Fischer 344 rats grow into epithelial cells in cultures and exhibit increased oxidative stress and reduced D1 receptor function

2008 ◽  
Vol 295 (5) ◽  
pp. C1326-C1331 ◽  
Author(s):  
Mohammad Asghar ◽  
Annirudha Chillar ◽  
Mustafa F. Lokhandwala
Keyword(s):  
Oxidative Stress ◽  
Primary Cultures ◽  
D1 Receptor ◽  
Zucker Rats ◽  
Receptor Function ◽  
Adult Rats ◽  
Fischer 344 ◽  
Old Rats ◽  
Obese Zucker Rats ◽  
F344 Rats

Earlier we reported defects in D1 receptor function in renal proximal tubules (RPTs) of aged Fischer 344 (F344) and obese Zucker rats. However, the defects in the receptor function in RPTs of obese Zucker rats do not pass onto primary cultures of RPTs from these animals. Here, we determined whether the defects in D1 receptor function in RPTs of aged F344 rats pass onto the primary cultures. RPTs from aged (24-mo) and adult (6-mo) F344 rats were grown into primary cultures. The microscopic studies showed that cells in cultures from adult and old rats were healthy as determined by the shape and size of the cells and nuclei. D1 receptor agonist SKF-38393 produced inhibition of 86Rb (rubidium) uptake, index of Na-K-ATPase activity, in cells from adult rats, but this was reduced in old rats. Also, SKF-38393 increased the [35S]GTPγS binding, index of receptor activation, in the membranes of cells from adult rats but to a lesser extent from old rats. Furthermore, there was a downward trend in the levels of D1 receptor numbers and in the receptor proteins in old rats. Interestingly, gp 91phox subunit of NADPH oxidase and cellular protein carbonyl levels (oxidative stress marker) were higher in cultures from old rats. These results show that RPTs from adult and old F344 rats grow into epithelial cells in cultures. Furthermore, cells in cultures from old rats are at a higher level of oxidative stress, which may be contributing to the reduced D1 receptor function in the cells from old compared with adult rats.

scholarly journals Exercise activates redox-sensitive transcription factors and restores renal D1 receptor function in old rats

2009 ◽  
Vol 297 (5) ◽  
pp. F1174-F1180 ◽  
Author(s):  
Liza George ◽  
Mustafa F. Lokhandwala ◽  
Mohammad Asghar
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
G Protein ◽  
Skf 38393 ◽  
Antioxidant Defenses ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Old Rats

We have previously reported that age-associated oxidative stress via protein kinase C (PKC) increases D1 receptor (D1R) phosphorylation and causes D1R-G protein uncoupling in renal proximal tubules (RPTs) of old Fischer 344 rats. This results in reduced ability of D1R agonist SKF-38393 to inhibit Na+-K+-ATPase in RPTs of old rats. Here, we studied the effect of treadmill exercise on markers of oxidative stress, PKC, D1R phosphorylation, D1R-G protein coupling, and Na+-K+-ATPase activity in RPTs of adult and old rats. We found increased levels of malondialdehyde, a marker of oxidative stress, in RPTs of old rats, which decreased during exercise. Nuclear levels of nuclear erythroid-related factor (Nrf)-2 and nuclear factor (NF)-κB in RPTs, transcription factors involved in antioxidant enzyme gene transcription, increased in exercised old rats. This was accompanied by an increase in the activity and expression of antioxidant enzymes, superoxide dismutase and heme oxygenase-1. Age-related decrease in the levels of D1R mRNAs and proteins was attenuated during exercise. Furthermore, exercise in old rats decreased PKC activity and D1R phosphorylation and increased SKF-38393-mediated [35S]guanosine 5′- O-(3-thiotriphosphate) binding (an index of D1R-G protein coupling). SKF-38393 also caused inhibition of Na+-K+-ATPase in these animals. Also, exercise caused a decrease in proteinuria and increase in phosphaturia in old rats. These results suggest beneficial effects of exercise in terms of increasing antioxidant defenses, decreasing oxidative stress, and improving kidney function in general and D1R function in particular in aging. Both Nrf-2 and NF-κB seem to play key role in this phenomenon.

Opioid-Activated Postsynaptic, Inward Rectifying Potassium Currents in Whole Cell Recordings in Substantia Gelatinosa Neurons

1998 ◽  
Vol 80 (6) ◽  
pp. 2954-2962 ◽  
Author(s):  
S. P. Schneider ◽  
W. A. Eckert ◽  
A. R. Light
Keyword(s):  
Membrane Potential ◽  
G Protein ◽  
Potassium Currents ◽  
Substantia Gelatinosa ◽  
Opioid Agonist ◽  
Membrane Hyperpolarization ◽  
Whole Cell ◽  
Protein Activation ◽  
G Protein Activation ◽  
Whole Cell Recordings

Schneider, S. P., W. A. Eckert III, and A. R. Light. Opioid-activated postsynaptic, inward rectifying potassium currents in whole cell recordings in substantia gelatinosa neurons. J. Neurophysiol. 80: 2954–2962, 1998. Using tight-seal, whole cell recordings from isolated transverse slices of hamster and rat spinal cord, we investigated the effects of the μ-opioid agonist (d-Ala2, N-Me-Phe4,Gly5-ol)-enkephalin (DAMGO) on the membrane potential and conductance of substantia gelatinosa (SG) neurons. We observed that bath application of 1–5 μM DAMGO caused a robust and repeatable hyperpolarization in membrane potential ( V m) and decrease in neuronal input resistance ( R N) in 60% (27/45) of hamster neurons and 39% (9/23) of rat neurons, but significantly only when ATP (2 mM) and guanosine 5′-triphosphate (GTP; 100 μM) were included in the patch pipette internal solution. An ED50 of 50 nM was observed for the hyperpolarization in rat SG neurons. Because G-protein mediation of opioid effects has been shown in other systems, we tested if the nucleotide requirement for opioid hyperpolarization in SG neurons was due to G-protein activation. GTP was replaced with the nonhydrolyzable GTP analogue guanosine-5′- O-(3-thiotriphosphate) (GTP-γ-S; 100 μM), which enabled DAMGO to activate a nonreversible membrane hyperpolarization. Further, intracellular application of guanosine-5′- O-(2-thiodiphosphate) (GDP-β-S; 500 μM), which blocks G-protein activation, abolished the effects of DAMGO. We conclude that spinal SG neurons are particularly susceptible to dialysis of GTP by whole cell recording techniques. Moreover, the depletion of GTP leads to the inactivation of G-proteins that mediate μ-opioid activation of an inward-rectifying, potassium conductance in these neurons. These results explain the discrepancy between the opioid-activated hyperpolarization in SG neurons observed in previous sharp electrode experiments and the more recent failures to observe these effects with whole cell patch techniques.

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