Sex and body-type interactions in the regulation of renal sodium transporter levels, urinary excretion, and activity in lean and obese Zucker rats.
ABSTRACT Female humans and rodents are relatively protected against the development of hypertension and renal disease. Whether this protection is modified during insulin resistance and obesity, however, is not known.
Because renal sodium reabsorption has a central role in determining blood pressure, we hypothesized that lean female rats would bave reduced renal expression, activity, and urinary excretion of 8 major sodium transporters/channels.
Lean and obese, male and female Zucker rats (n = 4-8 per group) were fed progressively higher levels of dietary NaCl over a period of 54 days. Urinary excretion of renal sodium transport proteins was determined for 3 different dietary levels (0.04%, 0.4%, and 4%) of NaCl. With the high-NaCl diet, natriuretic responses to benzamil, furosemide, and thiazide were used as in vivo markers for activity of the epithelial sodium channel (ENaC), the bumetanide-sensitive Na-K-2C1 cotransporter (NKCC2), and the thiazide-sensitive NaCl cotransporter (NCC), respectively.
Female rats (of both body types) had lower plasma renin activity and insulin levels than their male counterparts. Likewise, immunoblotting revealed female rats had increased whole kidney abundance of NCC and of the alpha, beta, and gamma subunits of ENaC, as well as decreased abundance of the type 3 sodium hydrogen exchanger (NHE3), type 2 sodium phosphate cotransporter (NaPi-2), and alpha-1 sodium-potassium-adenosine triphosphatase (Na-K-ATPase), compared with males. Obese rats had reduced levels of NKCC2, NHE3, and gamma-ENaC, but higher levels of NaPi-2 and NCC. Urine excretion of sodium transporters in lean female rats was nearly undetectable, whereas obese rats of both sexes excreted markedly more NKCC2 and NCC, which agreed with greater natriuretic responses to thiazide and furosemide.
Obese female rats are similar to lean female rats with regard to the sex-distinct pattern of renal sodium transporters. However, obese female rats are more like obese male rats with regard to increased natriuretic response tofurosemide and thiazide, and to urine excretion of several transporters including NCC. Our results suggest that, with obesity, there is some loss of the protective female advantage.
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ABSTRACT: Cardiovascular disease (CVD) is the primary cause of death in women, and women with type 2 diabetes mellitus are at greater risk of CVD compared with nondiabetic women. The increment in risk attributable to diabetes is greater in women than in men. The extent to which hyperglycemia contributes to heart disease risk has been examined in observational studies and clinical trials, although most included only men or did not analyze sex differences. The probable adverse influence of hyperglycemia is potentially mediated by impaired endothelial function, and/or by other mechanisms. Beyond high blood glucose level, a number of other common risk factors for CVD, including hypertension, dyslipidemia, and cigarette smoking, are seen in women with diabetes and require special attention. Presentation and diagnosis of CVD may differ between women and men, regardless of the presence of diabetes. Recognizing the potential for atypical presentation of CVD in women and the limitations of common diagnostic tools are important in preventing unnecessary delay in initiating proper treatment. Based on what we know today, treatment of CVD should be at least as aggressive in women-and especially in those with diabetes-as it is in men. Future trials should generate specific data on CVD in women, either by design of female-only studies or by subgroup analysis by sex.Archives of Internal Medicine 06/2004; 164(9):934-42. · 11.46 Impact Factor
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ABSTRACT: There are gender-associated differences in blood pressure (BP) in humans, with men having higher BP than age-matched pre-menopausal women and being at greater risk for cardiovascular and renal diseases. The mechanisms responsible for the gender differences in BP control and regulation are not clear, although there is some evidence that interactions between sex hormones and the kidneys could play a role. However, the response to salt in pre- and post-menopausal women, and in particular the influence of exogenous and endogenous female sex hormones on renal hemodynamics and tubular segmental sodium handling, have been poorly investigated. Recently we have shown that both endogenous and exogenous female sex hormones markedly influence the systemic and renal hemodynamic response to salt. We have found that BP in young normotensive women, regardless of oral contraceptive use, is rather insensitive to salt. However, the renal hemodynamic and the tubular responses to salt vary significantly during the normal menstrual cycle and with the administration of oral contraceptives. Furthermore, after the menopause, BP tends to become salt sensitive, a pattern that could be due to aging as well as to the modification of the sex hormone profile. These observations provide new insights pertaining to potential mechanisms explaining the lower incidence of cardiovascular disease and progression of renal disease in pre-menopausal women (which tend to disappear with the menopause); these observations also emphasize the importance of considering more carefully the phase of the menstrual cycle whenever conducting physiologic studies in women and enrolling women in clinical studies. Finally, increased salt sensitivity in menopausal women strongly encourages the use of diuretics.American Journal of Hypertension 11/2004; 17(10):994-1001. · 3.67 Impact Factor
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ABSTRACT: The phrase reactive oxygen species covers a number of molecules and atoms, including the quintessential member of the group, O2-; singlet oxygen; H2O2; organic peroxides; and OONO-. While nitric oxide (NO) is also technically a member of the reactive oxygen species family, it is generally considered with a different class of compounds and will not be considered here. To our knowledge, there are currently no published data reporting the effects of reactive oxygen species on net transepithelial flux in the proximal nephron. However, there is evidence that OONO- regulates Na+/K+ adenosine triphosphatase (ATPase) activity as well as paracellular permeability. While it is easy to speculate that such an effect on the pump would decrease net transepithelial solute and water reabsorption, one cannot do so without knowing how other transporters are affected. O2- stimulates NaCl absorption by the thick ascending limb by activating protein kinase C and blunting the effects of NO. The effects of O2- on thick ascending limb NaCl absorption may be important for the initiation of salt-sensitive hypertension. To our knowledge, there are no published data concerning the role of reactive oxygen species in the regulation of solute absorption in either the distal convoluted tubule or the collecting duct. However, OONO- inhibits basolateral K+ channels in the cortical collecting duct, although the net effect of such inhibition is unknown. CONCLUSION: While the regulation of tubular transport by reactive oxygen species is important to overall salt and water balance, we know very little about where and how these regulators act along the nephron.Acta Physiologica Scandinavica 12/2003; 179(3):225-32. · 2.55 Impact Factor