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.

Is angiotensin-(3–4) (Val-Tyr), the shortest angiotensin II-derived peptide, opening new vistas on the renin–angiotensin system?

“… 33 The idea of a common cell signaling mechanism receives further support because the counteracting effects of Ang-(3−4) are exerted against AT 1 R-mediated protein kinase C (PKC), one of the most important Ang II-stimulated modulators of transepithelial Na + fluxes in the kidney. 10 , 37 , 38 , 42 , 43 Although the actions of Ang-(3−4) in renal ion-transporting ATPases are significant when intrarenal Ang II levels are high, we should note the hierarchy in these effects: at very low (femtomolar) concentrations range, Ang-(3−4) reactivates the basolateral plasma membrane Ca 2+ -ATPase ( Figure 5(a) ), whereas nanomolar concentrations can inhibit Ang II-stimulated Na + -ATPase. 33 The resulting effect, requiring a continuous increase in Ang-(3−4) levels (formed from Ang II; Figure 4 ), would first lead in vivo to depressed intracellular Ca 2+ , diminished Ca 2+ -dependent PKC activity, recovery of lower basal Na + -pumping activity, and depressed active Na + flux towards the peritubular space.…”

Cilia-based peptidergic signaling

“…To attract sperm, echinoderm eggs release small soluble amidated peptides that bind with high affinity to sperm tail receptors. Vespids, injected wasp venom peptides with amidated C-termini, induce chemotaxis in polymorphonuclear leukocytes and macrophages, enhancing the inflammatory effects of hornet stings [58,59]. The Cre03.g204500 bioactive amidated product identified here is part of a large protein bound to the ectosome surface; whether this larger amidated product exhibits similar chemotactic properties to the GATI-amide peptide is uncertain.…”

Rats undernourished in utero have altered Ca2+signaling and reduced fertility in adulthood

“…The mean intensities of the normalized immunosignals from CTRL rats were considered to be 100%, and all data from CTRL and IM rats were expressed as percentages of this reference value, thus allowing the calculation of the SEM in CTRL conditions (Sahajpal and Ashton ; Silva et al. ).…”

“…The results are thus given as the ratio of the immunodetection intensity signal to the protein loading, which was expressed as percentage of the corresponding CTRL ratio. The mean intensities of the normalized immunosignals from CTRL rats were considered to be 100%, and all data from CTRL and IM rats were expressed as percentages of this reference value, thus allowing the calculation of the SEM in CTRL conditions (Sahajpal and Ashton 2005;Silva et al 2014b). species (Buege and Aust 1978) with slight method modifications , 2014Muzi-Filho et al 2013).…”