Altered signaling pathways linked to angiotensin II underpin the upregulation of renal Na+-ATPase in chronically undernourished rats

作者：Silva Paulo A; Muzi Filho Humberto; Pereira Acacio Amaury; Dias Juliana; Martins Joao F S; Landim Vieira Maicon; Verdoorn Karine S; Lara Lucienne S; Vieira Filho Leucio D; Cabral Edjair V; Paixao Ana D O; Vieyra Adalberto^*

来源：Biochimica et Biophysica Acta-Molecular Basis of Disease, 2014, 1842(12): 2357-2366.

DOI：10.1016/j.bbadis.2014.09.017

• Chronic undernutrition
• Tubulointerstitial Ang II
• PKC
• PKA
• Regulatory phosphorylation sites
• Kidney

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 V-max of the ouabain-resistant Na+-ATPase resident in the basolateral membranes increased %26gt;3-fold (P %26lt; 0.001) accompanied by an increase in Na+ affinity from 4.0 to 0.2 mM (P %26lt; 0.001). BRD rats had a %26gt;3-fold acceleration of the formation of phosphorylated intermediates in the early stage of the catalytic cycle (in the E-1 conformation) (P %26lt; 0.001). Immunostaining showed a huge increase in Ang II-positive cells in the cortical tubulointerstitium neighboring the basolateral membranes (%26gt;6-fold, P %26lt; 0.001). PKC isoforms (alpha, epsilon, lambda, zeta), Ang II type 1 receptors and PP2A were upregulated in BRD rats (in %): 55 (P %26lt; 0.001); 35 (P %26lt; 0.01); 125, 55, 11 and 30 (P %26lt; 0.001). PICA was downregulated by 55% (P %26lt; 0.001). With NetPhosK 1.0 and NetPhos 2.0, we detected 4 high-score (%26gt;0.70) regulatory phosphorylation sites for PKC and 1 for PKA in the primary sequence of the Na+-ATPase alpha-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.

• 出版日期2014-12