Sex‐linked differences in the course of chronic kidney disease and congestive heart failure: a study in 5/6 nephrectomized Ren‐2 transgenic hypertensive rats with volume overload induced using aorto‐caval fistula

Abstract

The role of hypertension and the renin-angiotensin system (RAS) in sex-related differences in the course of chronic kidney disease (CKD) and congestive heart failure (CHF) remain unclear, especially when the two diseases are combined. In male and female Ren-2 transgenic rats (TGR), a model of hypertension with activation of endogenous RAS, CKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of an aorto-caval fistula (ACF). The primary aim of the study was to examine long-term CKD- and CHF-related mortality, especially in animals with CKD and CHF combined, with particular interest in the potential sex-related differences. The follow-up period was 23 weeks after the first intervention (5/6 NX). We found, first, that TGR did not exhibit sexual dimorphism in the course of 5/6 NX-induced CKD. Second, in contrast, TGR exhibited important sex-related differences in the course of ACF-induced CHF-related mortality: intact female TGR showed higher survival rate than male TGR. This situation is reversed in the course of combined 5/6 NX-induced CKD and ACF-induced CHF-related mortality: intact female TGR exhibited poorer survival than male TGR. Third, the survival rate in animals with combined 5/6 NX-induced CKD and ACF-induced CHF was significantly worsened as compared with rat groups that were exposed to 'single organ disease'. Collectively, our present results clearly show that CKD aggravates long-term mortality of animals with CHF. In addition, TGR exhibit remarkable sexual dimorphism with respect to CKD- and CHF-related mortality, especially in animals with combined CKD and CHF.

Pharmacological Blockade of Soluble Epoxide Hydrolase Attenuates the Progression of Congestive Heart Failure Combined With Chronic Kidney Disease: Insights From Studies With Fawn-Hooded Hypertensive Rats

“…The beneficial effects of the treatment, particularly on the survival rate, were more pronounced in ACF FHH rats. In addition, our results show that, in accordance with previous findings (Oliver-Dussault et al, 2010; Melenovsky et al, 2012, 2018; Červenka et al, 2015, 2016; Kala et al, 2018), after creation of ACF the animals displayed signs of pronounced cardiac hypertrophy, involving both ventricles. Remarkably, this was associated with distinct lung congestion, indicating LV failure without signs of RV failure (no liver congestion).…”

“…Animals underwent either sham-operation or ACF creation as described above (at the week labeled -4) and were left without treatment for 4 weeks. Previous studies have shown that after this time CHF features are fully developed but the animals are still in the compensation phase (Oliver-Dussault et al, 2010; Melenovsky et al, 2012, 2018; Červenka et al, 2015, 2016; Kala et al, 2018). At this time point (week 0) the rats were divided into the following experimental groups:…”

“…Rats were anesthetized (tiletamine + zolazepam, Virbac SA, Carros Cedex, France, 8 mg/kg; and xylasine, Spofa, Czechia, 4 mg/kg intramuscularly) and CHF was induced by volume overload caused by ACF created using needle technique as employed and validated by many investigators including our own group (Oliver-Dussault et al, 2010; Abassi et al, 2011; Melenovsky et al, 2012, 2018; Cohen-Segev et al, 2014; Brower et al, 2015; Červenka et al, 2015, 2016; Kala et al, 2018). Briefly, after exposure of the abdominal aorta and inferior vena cava between the renal arteries and iliac bifurcation, the aorta was temporarily occluded at this segment for about 40 s. An 18-gauge needle (diameter 1.2 mm) was inserted into the abdominal aorta and advanced across its wall into the inferior vena cava to create ACF.…”

Effect of Angiotensin-Converting Enzyme Blockade, Alone or Combined With Blockade of Soluble Epoxide Hydrolase, on the Course of Congestive Heart Failure and Occurrence of Renal Dysfunction in Ren-2 Transgenic Hypertensive Rats With Aorto-Caval Fistula

“…The rat with aorto-caval fistula (ACF) presents a well-defined model of CHF dependent on volume overload, characterized also by activation of the systemic and intrarenal RAS, signs of cardiac remodeling as well as congestion and impairment of renal function. Thus, in many aspects the model reproduces the course of CHF in untreated human patients 21–24,30–35 .…”

“…The hypertensive rat transgenic for the mouse Ren-2 renin gene [TGR; strain name TGR(mRen2)27] presents a unique angiotensin II (ANG II)-dependent model of hypertension in which its development is attributed to a single gene alteration and to the augmented activation of endogenous RAS 36–38 . Thus, an experimental model of CHF that combines the well-recognized crucial detrimental factors promoting the progression of CHF is available and we have recently shown ACF TGR exhibit markedly increased CHF-related mortality as compared with the course in ACF Hannover Sprague-Dawley (HanSD) rats (transgene-negative, normotensive controls to TGR) 23,35 . We found that in addition to the increased RAS activity, ACF TGR also displayed tissue deficiency of biologically active fatty acid epoxides due to increased conversion of epoxyeicosatrienoic acids (EETs) [biologically active metabolites of cytochrome P450 (CYP)-dependent epoxygenase pathway of arachidonic acid (AA)] by soluble epoxide hydrolase (sEH) to biologically inactive dihydroxyeicosatrienoic acids (DHETEs).…”