Renal effects of prolonged high protein intake and COX2 inhibition on hypertensive rats with altered renal development

Abstract

Reverte V, Tapia A, Moreno JM, Rodríguez L, Salazar F, Llinás MT, Salazar FJ. Renal effects of prolonged high protein intake and COX2 inhibition on hypertensive rats with altered renal development. Am J Physiol Renal Physiol 301: F327-F333, 2011. First published May 25, 2011 doi:10.1152/ajprenal.00110.2011.-Cyclooxygenase 2 (COX2) is involved in regulating renal hemodynamics after renal ablation. It is also known that high protein intake (HPI) leads to a deterioration of renal function when there is preexisting renal disease and that there are important gender differences in the regulation of renal function. This study tested the hypothesis that the role of COX2 in regulating renal function and the renal hemodynamic effects elicited by HPI are enhanced when nephrogenesis is altered during renal development. It was also expected that the role of COX2 and the effects elicited by HPI are age and sex dependent. Newborn Sprague-Dawley rats were treated with an AT1 ANG II receptor antagonist during the nephrogenic period (ARAnp). Experiments were performed at 3-4 and 10 -11 mo of age. Arterial pressure was elevated (P Ͻ 0.05) at both ages and in both sexes of ARAnptreated rats. Renal COX2 expression was only elevated (P Ͻ 0.05) at 10 -11 mo of age in both sexes of ARAnp-treated rats. COX2 inhibition induced greater renal vasoconstriction in male and female hypertensive than in normotensive rats at both ages. HPI did not induce glomerular filtration rate (GFR) in the youngest hypertensive rats and in the oldest female hypertensive rats. However, the GFR decreased during HPI (0.63 Ϯ 0.07 to 0.19 Ϯ 0.05 ml/min) in the oldest male hypertensive rats. The HPI-induced increment in proteinuria was greater (P Ͻ 0.05) in male (99 Ϯ 22 mg/day) than in female (30 Ϯ 8 mg/day) hypertensive rats. These results show that COX2 plays an important role in the regulation of renal function when renal development is altered and that prolonged HPI can lead to a renal insufficiency in males but not in females with reduced nephron endowment.hypertension; proteinuria; renal function SEVERAL STUDIES HAVE PROPOSED that an alteration in nephrogenesis leads to a compensatory glomerular hypertrophy and an accelerated deterioration of renal function that are sex dependent (2,8,21,31). It has been reported that the compensatory glomerular changes that occur in male animals after subtotal ablation of renal mass are mediated by an increase in cyclooxygenase 2 (COX2) activity (7,27). However, it is unknown to what extent COX2 is involved in the regulation of renal function when nephron endowment decreases during renal development and whether this importance of COX2 is greater in males than in females. One hypothesis tested in this study is that COX2-derived metabolites are involved in the regulation of renal function when nephrogenesis is altered during the late nephrogenic period and that the role of COX2 is sex and aging dependent. A sex-dependent difference was expected since it has been reported in other mechanisms involved in the regulation of ren...

Sex differences in developmental programming models

“…Direct comparisons between male and female offspring have been made predominantly in rats (Langley-Evans et al 1996, Ozaki et al 2001, Khan et al 2003, Nivoit et al 2009, Reverte et al 2011, but sex-specific differences are also reported in mice (Gallou-Kabani et al 2010, Vickers et al 2011; see Table 1). There is evidence that male rat offspring are more susceptible to developmentally programmed hypertension than female offspring in studies where the sexes are directly compared (Langley-Evans et al 1996, Kwong et al 2000, Dodic et al 2002, Alexander 2003, Woods et al 2005, Maloney et al 2011).…”

“…The attenuation of the endothelial response to acetylcholine induced by this model was, however, present in both male and female offspring. In keeping with the predominantly male hypertensive effects of prenatal insults on development, studies have found more impaired renal function in male than in female rat offspring (Woods et al 2005, Gilbert et al 2007, Reverte et al 2011. Focusing on studies where the sexes are compared directly within the same model, it has been suggested that an anatomical basis for impaired renal function can be seen in a direct reduction of the number of nephrons in male offspring (Woods et al 2005).…”

Association of Short-Term Use of Nonsteroidal Anti-Inflammatory Drugs With Stroke in Patients With Hypertension

“…First, previous studies have documented that NSAIDs, to some extent, have an impact on vasoconstriction and sodium excretion, which can increase blood pressure and subsequently lead to an increased risk of cerebrovascular events. [21][22][23] Second, NSAIDs inhibit the activity of the COX isozymes (COX-1 and COX-2) and block prostanoid biosynthesis. As a result, NSAIDs decrease total renal perfusion and lead to redistribution of renal blood flow, particularly in vulnerable populations, which may cause medullary ischemia and even acute renal failure.…”

Postnatal regulation of 15-hydroxyprostaglandin dehydrogenase in the rat kidney

“…Nephrogenesis in rodents continues after birth. Abundant evidence suggests an essential role of COX-2 in postnatal kidney development (12,26). COX-2 null mice developed impairment in maturation of the nephrogenic zone during the postnatal period, leading to chronic renal failure and hypertension (2,10,17).…”