title: 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.
abstract: 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.
authors.affiliation: Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, TX 77204, USA.
authors.forename: Riham Zein
authors.initials: RZ
authors.lastname: Fardoun
authors.forename: Mohammad
authors.initials: M
authors.lastname: Asghar
authors.forename: Mustafa
authors.initials: M
authors.lastname: Lokhandwala
mesh_terms: 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
chemical_list: 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