In the present study, we investigated the development of hypertension in prenatally undernourished adult rats, including the mechanisms that culminate in dysfunctions of molecular signalling in the kidney. Dams were fed a low-protein multideficient diet throughout gestation with or without a-tocopherol during lactation. The time course of hypertension development followed in male offspring was correlated with alterations in proximal tubule Na þ -ATPase activity, expression of angiotensin II (Ang II) receptors, and activity of protein kinases C and A. After the establishment of hypertension, Ang II levels, cyclo-oxygenase 2 (COX-2) and NADPH oxidase subunit expression, lipid peroxidation and macrophage infiltration were examined in renal tissue. Lipid peroxidation in undernourished rats, which was very intense at 60 d, decreased at 90 d and returned to control values by 150 d. During the prehypertensive phase, prenatally undernourished rats exhibited elevated renal Na þ -ATPase activity, type 2 Ang II receptor down-regulation and altered protein kinase A:protein kinase C ratio. Stable late hypertension coexisted with highly elevated levels of Ang II-positive cells in the cortical tubulointerstitium, enhanced increase in the expression of p47 phox (NADPH oxidase regulatory subunit), marked down-regulation of COX-2 expression, expanded plasma volume and decreased creatinine clearance. These alterations were reduced when the dams were given a-tocopherol during lactation. The offspring of well-nourished dams treated with a-tocopherol exhibited most of the alterations encountered in the offspring of undernourished dams not treated with a-tocopherol. Thus, alterations in proximal tubule Na þ transport, subcellular signalling pathways and reactive oxygen species handling in renal tissue underpin the development of hypertension.
We investigated whether hypertension induced by maternal lipopolysaccharide (LPS) administration during gestation is linked to peripheral vascular and renal hemodynamic regulation, through angiotensin II → NADPH-oxidase signalling, and whether these changes are directly linked to intrauterine oxidative stress. Female Wistar rats were submitted to LPS, in the absence or presence of α-tocopherol during pregnancy. Malondialdehyde in placenta and in livers from dams and foetuses was enhanced by LPS. Tail-cuff systolic blood pressure (tcSBP) was elevated in the 16-week-old LPS offspring. Renal malondialdeyde and protein expression of NADPH oxidase isoform 2 were elevated in these animals at 20 weeks of age. Maternal α-tocopherol treatment prevented the elevation in malondialdehyde induced by LPS on placenta and livers from dams and foetuses, as well as prevented the elevation in tcSBP and the elevation in renal malondialdehyde in adult life. LPS offspring presented impairment of endothelium-dependent relaxation in aorta and mesenteric rings, which was blunted by angiotensin type 1 receptor (ATR) blockade and NADPH oxidase inhibition. At age of 32 weeks, renal hemodynamic parameters were unchanged in anaesthetised LPS offspring, but angiotensin II infusion led to an increased glomerular filtration rate paralleled by filtration fraction elevation. The renal haemodynamic changes provoked by angiotensin II was prevented by early treatment with α-tocopherol and by late treatment with NADPH oxidase inhibitor. These results point to oxidative stress as a mediator of offspring hypertension programmed by maternal inflammation and to the angiotensin II → NADPH oxidase signalling pathway as accountable for vascular and renal dysfunctions that starts and maintains hypertension.
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.
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