Renal molecular mechanisms underlying altered Na⁺handling and genesis of hypertension during adulthood in prenatally undernourished rats

Abstract

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.

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

“…Overall, this ensemble of data, as well as others from studies with contrasting results depending on the restriction type and window [10,33,[51][52][53][54], nevertheless converges to support the idea that deficient diets -especially those containing low protein -can disrupt the physiological interactions between RAS and renal Na + handling. Here, we provide evidence that this disruption is probably due to a local increase in Ang II, which can be considered a response to compensate (inappropriately) for the reduced renal mass, to increase the Na + -associated proximal reabsorption of a reduced pool of amino acids [5] and also to restore the impaired capacity to concentrate urine [45].…”

“…We recently demonstrated that chronically undernourished rats present simultaneous losartan-sensitive alterations in renal and cardiac Na + handling [5], in which upregulation of the recently cloned and purified ouabain-resistant, furosemide-inhibitable Na + -ATPase is pivotal [6,7]. This pump is considered to be the fine-tune mechanism of Na + reabsorption by proximal tubule cells [8], and its altered kinetic and regulatory properties constitute a hallmark of kidney alterations that involve deregulated local angiotensin II (Ang II) levels, inflammation and reactive oxygen species (ROS) signaling [9,10].…”

“…Ang II is one of the most important modulators of the renal ouabainresistant Na + -ATPase from proximal tubule cells, acting on a signaling cascade involving both Ang II receptors, PKA and PKC [10][11][12][13]. This pathway seems to be affected in intrauterine, perinatal and chronic undernutrition [5,12,14].…”

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

“…Lipid peroxidation was assessed in freshly removed whole vas deferens by measuring thiobarbituric acid reactive species (Buege and Aust ) with slight method modifications (Vieira‐Filho et al. , ; Muzi‐Filho et al. ).…”

A Calcium-Deficient Diet in Rat Dams during Gestation Decreases HOMA-β% in 3 Generations of Offspring

“…In a number of animal models, the offspring of mothers given poor nutrition during pregnancy exhibit pathophysiological changes similar to those observed in human diseases [12,13,14]. Some experimental and observational findings from humans and other animals indicate an association between maternal Ca intake during pregnancy and blood pressure in offspring [15,16], while others do not [17].…”