Role of nuclear factor kappa B (NF-kappaB) in oxidative stress-induced defective dopamine D1 receptor signaling in the renal proximal tubules of Sprague-Dawley rats.
Dopamine promotes sodium excretion, in part, via activation of D1 receptors in renal proximal tubules (PT) and subsequent inhibition of Na, K-ATPase. Recently, we have reported that oxidative stress causes D1 receptor-G-protein uncoupling via mechanisms involving protein kinase C (PKC) and G-protein-coupled receptor kinase 2 (GRK 2) in the primary cultures of renal PT of Sprague-Dawley (SD) rats. There are reports suggesting that redox-sensitive nuclear transcription factor, NF-kappaB, is activated in conditions associated with oxidative stress. This study was designed to identify the role of NF-kappaB in oxidative stress-induced defective renal D1 receptor-G-protein coupling and function. Treatment of the PT with hydrogen peroxide (H(2)O(2), 50 microM/20 min) induced the nuclear translocation of NF-kappaB, increased PKC activity, and triggered the translocation of GRK 2 to the proximal tubular membranes. This was accompanied by hyperphosphorylation of D1 receptors and defective D1 receptor-G-protein coupling. The functional consequence of these changes was decreased D1 receptor activation-mediated inhibition of Na, K-ATPase activity. Interestingly, pretreatment with pyrrolidine dithiocarbamate (PDTC, 25 microM/10 min), an NF-kappaB inhibitor, blocked the H(2)O(2)-induced nuclear translocation of NF-kappaB, increase in PKC activity, and GRK 2 translocation and hyperphosphorylation of D1 receptors in the proximal tubular membranes. Furthermore, PDTC restored D1 receptor G-protein coupling and D1 receptor agonist-mediated inhibition of the Na, K-ATPase activity. Therefore, we suggest that oxidative stress causes nuclear translocation of NF-kappaB in the renal proximal tubules, which contributes to defective D1 receptor-G-protein coupling and function via mechanisms involving PKC, membranous translocation of GRK 2, and subsequent phosphorylation of dopamine D1 receptors.
Fardoun
Riham Zein
RZ
Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, TX 77204, USA.
Asghar
Mohammad
M
Lokhandwala
Mustafa
M
D000818:Animals; D004298:Dopamine / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress; D010766:Phosphorylation; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry; D013312:Stress, Physiological; D013859:Thiocarbamates / Q000494:pharmacology
D016328:NF-kappa B; D017447:Receptors, Dopamine D1; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D011392:Proline; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; D004298:Dopamine