title: Altered signaling pathways linked to angiotensin II underpin the upregulation of renal Na(+)-ATPase in chronically undernourished rats.
abstract: This study has investigated the participation of altered signaling linked to angiotensin II (Ang II) that could be associated with increased Na(+) reabsorption in renal proximal tubules during chronic undernutrition. A multideficient chow for rats (basic regional diet, BRD) was used, which mimics several human diets widely taken in developing countries. The Vmax of the ouabain-resistant Na(+)-ATPase resident in the basolateral membranes increased >3-fold (P<0.001) accompanied by an increase in Na(+) affinity from 4.0 to 0.2mM (P<0.001). BRD rats had a >3-fold acceleration of the formation of phosphorylated intermediates in the early stage of the catalytic cycle (in the E1 conformation) (P<0.001). Immunostaining showed a huge increase in Ang II-positive cells in the cortical tubulointerstitium neighboring the basolateral membranes (>6-fold, P<0.001). PKC isoforms (α, ε, λ, ζ), Ang II type 1 receptors and PP2A were upregulated in BRD rats (in %): 55 (P<0.001); 35 (P<0.01); 125, 55, 11 and 30 (P<0.001). PKA was downregulated by 55% (P<0.001). With NetPhosK 1.0 and NetPhos 2.0, we detected 4 high-score (>0.70) regulatory phosphorylation sites for PKC and 1 for PKA in the primary sequence of the Na(+)-ATPase α-subunit, which are located in domains that are key for Na(+) binding and catalysis. Therefore, chronic undernutrition stimulates tubulointerstitial activity of Ang II and impairs PKC- and PKA-mediated regulatory phosphorylation, which culminates in an exaggerated Na(+) reabsorption across the proximal tubular epithelium.
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil; National Institute of Science and Technology for Structural Biology and Bioimaging, 21941-902 Rio de Janeiro, Brazil.
authors.forename: Paulo A
authors.initials: PA
authors.lastname: Silva
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil; National Institute of Science and Technology for Structural Biology and Bioimaging, 21941-902 Rio de Janeiro, Brazil.
authors.forename: Humberto
authors.initials: H
authors.lastname: Muzi-Filho
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil; National Institute of Science and Technology for Structural Biology and Bioimaging, 21941-902 Rio de Janeiro, Brazil.
authors.forename: Amaury
authors.initials: A
authors.lastname: Pereira-Acácio
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil; National Institute of Science and Technology for Structural Biology and Bioimaging, 21941-902 Rio de Janeiro, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Dias
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil; National Institute of Science and Technology for Structural Biology and Bioimaging, 21941-902 Rio de Janeiro, Brazil.
authors.forename: João F S
authors.initials: JF
authors.lastname: Martins
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil; National Institute of Science and Technology for Structural Biology and Bioimaging, 21941-902 Rio de Janeiro, Brazil.
authors.forename: Maicon
authors.initials: M
authors.lastname: Landim-Vieira
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil; National Institute of Science and Technology for Structural Biology and Bioimaging, 21941-902 Rio de Janeiro, Brazil.
authors.forename: Karine S
authors.initials: KS
authors.lastname: Verdoorn
authors.affiliation: National Institute of Science and Technology for Structural Biology and Bioimaging, 21941-902 Rio de Janeiro, Brazil; Institute of Biomedical Sciences, Federal University of Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil.
authors.forename: Lucienne S
authors.initials: LS
authors.lastname: Lara
authors.affiliation: National Institute of Science and Technology for Structural Biology and Bioimaging, 21941-902 Rio de Janeiro, Brazil; Department of Physiology and Pharmacology, Federal University of Pernambuco, 50670-901 Recife, Brazil.
authors.forename: Leucio D
authors.initials: LD
authors.lastname: Vieira-Filho
authors.affiliation: National Institute of Science and Technology for Structural Biology and Bioimaging, 21941-902 Rio de Janeiro, Brazil; Department of Physiology and Pharmacology, Federal University of Pernambuco, 50670-901 Recife, Brazil.
authors.forename: Edjair V
authors.initials: EV
authors.lastname: Cabral
authors.affiliation: National Institute of Science and Technology for Structural Biology and Bioimaging, 21941-902 Rio de Janeiro, Brazil; Department of Physiology and Pharmacology, Federal University of Pernambuco, 50670-901 Recife, Brazil.
authors.forename: Ana D O
authors.initials: AD
authors.lastname: Paixão
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil; National Institute of Science and Technology for Structural Biology and Bioimaging, 21941-902 Rio de Janeiro, Brazil. Electronic address: avieyra@biof.ufrj.br.
authors.forename: Adalberto
authors.initials: A
authors.lastname: Vieyra
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005665:Furosemide / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000201:enzymology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D007700:Kinetics; D008297:Male; D044342:Malnutrition / Q000378:metabolism / Q000503:physiopathology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010042:Ouabain / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D027682:Cation Transport Proteins; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D010042:Ouabain; D005665:Furosemide; D012964:Sodium; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D000251:Adenosine Triphosphatases; C021838:sodium-translocating ATPase
keywords: Chronic undernutrition; Kidney; PKA; PKC; Regulatory phosphorylation sites; Tubulointerstitial Ang II