Sex differences in baroreflex sensitivity, heart rate variability, and end organ damage in the TGR(mRen2)27 rat

Abstract

The aim of this investigation was to evaluate sex differences in baroreflex and heart rate variability (HRV) dysfunction and indexes of end-organ damage in the TG(mRen2)27 (Ren2) rat, a model of renin overexpression and tissue renin-angiotensin-aldosterone system overactivation. Blood pressure (via telemetric monitoring), blood pressure variability [BPV; SD of systolic blood pressure (SBP)], spontaneous baroreflex sensitivity, HRV [HRV Triangular Index (HRV-TI), standard deviation of the average NN interval (SDNN), low and high frequency power (LF and HF, respectively), and Poincaré plot analysis (SD1, SD2)], and cardiovascular function (pressure-volume loop analysis and proteinuria) were evaluated in male and female 10-wk-old Ren2 and Sprague Dawley rats. The severity of hypertension was greater in Ren2 males (R2-M) than in Ren2 females (R2-F). Increased BPV, suppression of baroreflex gain, decreased HRV, and associated end-organ damage manifested as cardiac dysfunction, myocardial remodeling, elevated proteinuria, and tissue oxidative stress were more pronounced in R2-M compared with R2-F. During the dark cycle, HRV-TI and SDNN were negatively correlated with SBP within R2-M and positively correlated within R2-F; within R2-M, these indexes were also negatively correlated with end-organ damage [left ventricular hypertrophy (LVH)]. Furthermore, within R2-M only, LVH was strongly correlated with indexes of HRV representing predominantly vagal (HF, SD1), but not sympathetic (LF, SD2), variability. These data demonstrated relative protection in females from autonomic dysfunction and end-organ damage associated with elevated blood pressure in the Ren2 model of hypertension.

Salt Loading Promotes Kidney Injury via Fibrosis in Young Female Ren2 Rats

“…In summary, data from our current investigation denote that salt induces proteinuria and fibrosis without changes in systolic pressure in young female nonobese insulin-resistant Ren2 rats [12,16]. Our data suggest for the first time an important role for gender in processes such as EMT or even EndMT.…”

“…To this end, others and we have previously observed in a model of RAAS overactivation that there exists dimorphism in blood pressure and proteinuria responses between males and females [12,13]. In this regard, the differences observed in proteinuria between female and male congenic mRen(2)27 (Ren2):Lewis rats were overcome by administering excess salt.…”

“…In order to address the effect of increased dietary salt intake on proteinuria and interstitial fibrosis in female rats, we utilized the transgenic Ren2 rat that overexpresses the mouse renin transgene and manifests elevated plasma aldosterone levels as well as increased kidney tissue Ang II. The female Ren2 rat exhibits normal body mass, but develops insulin resistance and hypertension, yet little proteinuria [12,15,16]. Therefore, to investigate the impact of increased dietary salt on the female kidney structure and function, we fed female Ren2 rats with a high-salt diet over 3 weeks and examined proteinuria along with structural abnormalities associated with progressive kidney disease.…”

Cardiovascular Autonomic Dysfunction in Chronic Kidney Disease: a Comprehensive Review

“…On the other hand, HRV and HR BRS are markedly lower in hypertensive women than in hypertensive men [183]. However, in rat and mouse models of hypertension, females show lower or unchanged resting HR, greater HRV and HR BRS, lower resting BP and BP variability, and/or lower sympathetic vasomotor tone, as assessed by ganglionic blockade [181,184].…”

Identification of Bona Fide Alternative Renin Transcripts Expressed Along Cortical Tubules and Potential Roles in Promoting Insulin Resistance In Vivo Without Significant Plasma Renin Activity Elevation

“…In earlier days, it was demonstrated that enhanced kinetics of the reaction between mouse renin and rat angiotensinogen are one of pathophysiological mechanism for this model. 39,40 Recently, this animal model was reported to have various pathophysiological features such as insulin resistance, [41][42][43] left ventricular dysfunction, 44,45 nonalcoholic fatty liver disease-like significant hepatic steatosis with increased hepatic reactive oxygen species, lipid peroxidation, steatohepatitis, and fibrosis 46 as a result of tissue RAS overactivation. We generated transgenic ARen2 overexpression mice with a C57BL/6J background, which endogenously have only the Ren1C renin gene.…”