Prenatal Undernutrition Changes Renovascular Responses of Nimesulide in Rat Kidneys

Abstract

Several studies in the Northeastern region of Brazil have demonstrated an association between hypertension in adult populations and prenatal and postnatal undernutrion. The central hypothesis we proposed was that hypertension could be favoured by programmed alterations in branches of the renal arachidonic pathway and consequently in counter-balancing the renin angiotensin system, especially during treatments with cyclooxygenase inhibitors. We assessed the influence of subchronic (21 days) and acute administration of nimesulide, a preferential cyclooxygenase-2 (COX-2) inhibitor, on mean blood pressure (MAP), renal blood flow (RBF), glomerular filtration rate (GFR) and urinary output (U v ) in adult rats that were prenatally undernourished. Undernutrition per se led to the onset of mild hypertension in adult offspring, whereas subchronic nimesulide treatment increased MAP in control and elicited further augmentation in undernourished animals. The drug (i) decreased RBF and GFR in controls by 50%, whereas no effect was detected in the undernourished group, and (ii) increased U v by 25% in controls, an effect that was potentiated by 200% in programmed animals. In contrast, acute nimesulide administration decreased U v , with the hypertensive effect of the drug being potentiated during dehydration. These findings demonstrate that prenatal nutritional programming differentially modulates adult renovascular responses to nimesulide in the cortex and medulla, which may exacerbate the deleterious effects of COX-2 inhibition in the kidney.Epidemiological studies indicate an association between undernutrition in early life and hypertension in adults in rural areas of Northeast Brazil [1]. Experimental undernutrition using a diet mimicking that widely used by human beings in these regions [2] leads to alterations in renal structure and function [3], including those related to angiotensin II-modulated renal fluid handling [4] that could be associated with the onset of hypertension in adulthood. Maternal dietary restriction using different protocols has demonstrated programming of renal lesions in cortex and medulla that could be involved in alterations of renovascular responses [5][6][7], although the role of the kidney in perinatal programming of long-term alterations of arterial blood pressure has had only minor attention until recently [8].Since the intrarenal renin ⁄ angiotensin II system might be modulated by arachidonic acid-derived vasoactive products reviewed in [9,10], we have postulated that programming of adult hypertension could also involve alterations in key steps of the renal arachidonic pathway, such as those mediated by cyclooxygenases. Consequently, the renovascular responses of adults become altered after undernourishment in early life. We also hypothesized that possible hidden alteration in the intrarenal arachidonic acid routes could be exacerbated during the treatment with cyclooxygenase inhibitors.The adult kidney is one of the few organs that constitutively produce cyclooxygenase-2 (COX-2), a...

Alpha-tocopherol prevents intrauterine undernutrition-induced oligonephronia in rats

“…These elevated levels are maintained at 25 days of age (Fig. 6b), reflecting the levels in the maternal liver [10,16], and continue to be elevated at the juvenile [25] and adult [3,10,16] stages. In a recent report, Shen and coworkers demonstrated that the kidneys of prenatally undernourished rats have a differentiated profile of Fig.…”

“…P<0.05: * vs C group, † vs CTP group, ‡ vs U group. c and d are representative fields (× 280) of α-SMA staining in kidneys from C and U group rats respectively Taking into account the action of prenatal undernutrition on lipid peroxidation [3,10,16] and the fact that α-tocopherol acts, at least in part, by scavenging peroxyl radicals [34], the liver was used to investigate oxidative stress. Figure 6a and b demonstrate that hepatic TBARS levels (production of malondialdehyde) were increased (P< 0.05) in 1-and 25-day-old rats from the U group.…”

“…Malnutrition was induced through a deficient diet as described previously [3,8,10,16]. The ingredients of the diet (g/g%) were beans (18.3), manioc flour (64.8), jerked meat (3.7), and sweet potato (12.8), which were cooked, dehydrated at 60°C, and pulverized.…”

“…Oxidative stress, which is a factor that could intervene with nephrogenesis, is increased in the kidney [3,9,25] and in the vascular endothelium [26] from intrauterine undernourished rats. Intrauterine malnutrition-programmed oxidative stress disrupts Ang II downstream signaling, and this can be reversed by α-tocopherol administration during lactation [16], providing clear evidence that prenatal programming of the molecular action of Ang II could be reprogrammed.…”

“…Intrauterine undernutrition can lead to hypertension [1][2][3] and microalbuminuria [4,5] due to impaired nephrogenesis [2,[6][7][8] and molecular changes that affect renal tubular sodium reabsorption [9,10]. Maternal undernutritioninduced oligonephronia is associated with reduced expression of renin-angiotensin system (RAS) components in the kidneys of neonates [11], increased apoptosis in the mesenchyme of the embryonic metanephros (the precursor of the adult mammalian kidney) at the start of nephrogenesis [12], and reduced expression of glial cell-derived neurotrophic factor (GDNF), a crucial growth factor for ureteric bud proliferation [13].…”