Sex Differences in the Renal Vascular Responses of AT1 and Mas Receptors in Two-Kidney-One-Clip Hypertension

Background The prevalence and severity of hypertension, as well as the activity of the systemic and local renin angiotensin systems (RASs), are gender related, with more symptoms in males than in females. However, the underlying mechanisms are not well understood. In this study, we investigated sex differences in renal vascular responses to angiotensin II (Ang II) administration with and without Ang II type 1 and Mas receptor (AT1R and MasR) antagonists (losartan and A779) in the 2K1C rat model of renovascular hypertension. Methods Male and female 2K1C rats were divided into 8 experimental groups (4 of each sex) treated with vehicle, losartan, A779, or A779+losartan. Responses of mean arterial pressure (MAP), renal blood flow (RBF), and renal vascular resistance (RVR) to Ang II were determined. Results In both sexes, the basal MAP, RBF, and RVR were not significantly different between the four groups during the control period. The Ang II administration decreased RBF and increased RVR in a dose-related manner in both sexes pretreated with vehicle or A779 (Pdose < 0.0001), but in vehicle pretreated groups, RBF and RVR responses were different between male and female rats (Pgroup < 0.05). AT1R blockade increased RBF and decreased RVR responses to Ang II, and no difference between the sexes was detected. Coblockades of AT1R and MasR receptors increased RBF response to Ang II significantly in males alone but not in females (Pgroup=0.04). Conclusion The impact of Ang II on RBF and RVR responses seems to be gender related with a greater effect on males, and this sex difference abolishes by Mas receptor blockade. However, the paradoxical role of dual losartan and A779 may provide the different receptor interaction in RAS between male and female rats.

[1]  M. Nematbakhsh,et al.  Mas receptor antagonist (A799) alters the renal hemodynamics responses to angiotensin II administration after renal moderate ischemia/reperfusion in rats: gender related differences , 2019, Research in pharmaceutical sciences.

[2]  X. Li,et al.  Intratubular and intracellular renin-angiotensin system in the kidney: a unifying perspective in blood pressure control. , 2018, Clinical science.

[3]  Robert Carey,et al.  Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Synopsis of the 2017 American College of Cardiology/American Heart Association Hypertension Guideline , 2018, Annals of Internal Medicine.

[4]  Jie Zhang,et al.  Role of Kidneys in Sex Differences in Angiotensin II–Induced Hypertension , 2017, Hypertension.

[5]  E. Johns,et al.  Intrarenal Mas and AT1 receptors play a role in mediating the excretory actions of renal interstitial angiotensin‐(1–7) infusion in anaesthetized rats , 2017, Experimental physiology.

[6]  U. Steckelings,et al.  Angiotensin II Type 2 Receptor and Receptor Mas Are Colocalized and Functionally Interdependent in Obese Zucker Rat Kidney , 2017, Hypertension.

[7]  L. Navar,et al.  Increased angiotensinogen expression, urinary angiotensinogen excretion, and tissue injury in nonclipped kidneys of two-kidney, one-clip hypertensive rats. , 2016, American journal of physiology. Renal physiology.

[8]  Se-Yun Kim,et al.  Sequential activation of the intrarenal renin-angiotensin system in the progression of hypertensive nephropathy in Goldblatt rats. , 2016, American journal of physiology. Renal physiology.

[9]  Mark D. Huffman,et al.  Heart Disease and Stroke Statistics—2016 Update: A Report From the American Heart Association , 2016, Circulation.

[10]  F. Sánchez-Muñoz,et al.  Changes in protein and gene expression of angiotensin II receptors (AT1 and AT2) in aorta of diabetic and hypertensive rats , 2016, Clinical and experimental hypertension.

[11]  V. Lemos,et al.  Mas receptor overexpression increased Ang-(1–7) relaxation response in renovascular hypertensive rat carotid , 2015, Peptides.

[12]  J. Sullivan,et al.  Differences in angiotensin (1-7) between men and women. , 2015, American journal of physiology. Heart and circulatory physiology.

[13]  Jackson T. Wright,et al.  2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). , 2014, JAMA.

[14]  J. Sullivan,et al.  Hypertension: what's sex got to do with it? , 2013, Physiology.

[15]  G. Leoncini,et al.  Blood pressure variability and multiple organ damage in primary hypertension , 2013, Journal of Human Hypertension.

[16]  M. Nematbakhsh,et al.  Sex differences in the renal vascular response to angiotensin II involves the Mas receptor , 2012, Acta physiologica.

[17]  Chen Yu,et al.  Counteraction between angiotensin II and angiotensin-(1–7) via activating angiotensin type I and Mas receptor on rat renal mesangial cells , 2012, Regulatory Peptides.

[18]  I. Pastan,et al.  Liver angiotensinogen is the primary source of renal angiotensin II. , 2012, Journal of the American Society of Nephrology : JASN.

[19]  K. Denton,et al.  Postnatal ontogeny of angiotensin receptors and ACE2 in male and female rats. , 2012, Gender medicine.

[20]  Hong Ma,et al.  Regulation of angiotensin-converting enzyme 2 and Mas receptor by Ang-(1–7) in heart and kidney of spontaneously hypertensive rats , 2011, Journal of the renin-angiotensin-aldosterone system : JRAAS.

[21]  M. Nematbakhsh,et al.  Gender Differences in Pressure-Natriuresis and Renal Autoregulation: Role of the Angiotensin Type 2 Receptor , 2011, Hypertension.

[22]  H. Siragy,et al.  Angiotensin AT2 Receptor Stimulation Inhibits Early Renal Inflammation in Renovascular Hypertension , 2011, Hypertension.

[23]  H. Kobori,et al.  Reciprocal changes in renal ACE/ANG II and ACE2/ANG 1-7 are associated with enhanced collecting duct renin in Goldblatt hypertensive rats. , 2011, American journal of physiology. Renal physiology.

[24]  Tatsuo Yamamoto,et al.  Angiotensin (1-7) Receptor Antagonism Equalizes Angiotensin II-Induced Hypertension in Male and Female Spontaneously Hypertensive Rats , 2010, Hypertension.

[25]  R. Toto,et al.  Dual blockade of the renin-angiotensin-aldosterone system: beyond the ACE inhibitor and angiotensin-II receptor blocker combination. , 2009, American journal of hypertension.

[26]  K. Denton,et al.  Enhanced Angiotensin II Type 2 Receptor Mechanisms Mediate Decreases in Arterial Pressure Attributable to Chronic Low-Dose Angiotensin II in Female Rats , 2008, Hypertension.

[27]  M. Hudson,et al.  Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure — A population study , 2007, European journal of heart failure.

[28]  G. Leoncini,et al.  Serum Uric Acid and Target Organ Damage in Primary Hypertension , 2005, Hypertension.

[29]  I. Armando,et al.  Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat , 2005, Regulatory Peptides.

[30]  M. Burnier,et al.  Gender difference in the response to an angiotensin-converting enzyme inhibitor and a diuretic in hypertensive patients of African descent , 2004, Journal of hypertension.

[31]  Z. Fortes,et al.  A lower ratio of AT1/AT2 receptors of angiotensin II is found in female than in male spontaneously hypertensive rats. , 2004, Cardiovascular research.

[32]  C. Bulpitt,et al.  Systolic blood pressure variability as a risk factor for stroke and cardiovascular mortality in the elderly hypertensive population , 2003, Journal of hypertension.

[33]  H. Kobori,et al.  Regulation of intrarenal angiotensin II in hypertension. , 2002, Hypertension.

[34]  E. Sonnenblick,et al.  Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure. , 2000, Circulation.

[35]  F. Amiri,et al.  Renal angiotensin II receptor regulation in two-kidney, one clip hypertensive rats: effect of ACE inhibition. , 1997, Hypertension.

[36]  Y. H. Lee,et al.  RESEARCH Sex and Gender in Renal Health and Function Sex-related differences in the intratubular renin-angiotensin system in two-kidney, one-clip hypertensive rats , 2019 .

[37]  Philippe Van De Borne,et al.  Guidelines for the management of arterial hypertension , 2014 .

[38]  R. Johns,et al.  Differential regulation of renal angiotensin subtype AT1A and AT2 receptor protein in rats with angiotensin-dependent hypertension. , 1999, Hypertension.