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• W2008806257 abstract "Diabetes mellitus is associated with natriuresis, whereas estrogen has been shown to be renoprotective in diabetic nephropathy and may independently regulate renal sodium reabsorption. The aim of this study was to determine the effects of 17-β estradiol (E2) replacement to diabetic, ovariectomized (OVX) female rats on the expression of major renal sodium transporters. Female, Sprague–Dawley rats (210 g) were randomized into four groups: (1) OVX; (2) OVX+E2; (3) diabetic+ovariectomized (D+OVX); and (4) diabetic+ovariectomized+estrogen (D+OVX+E2). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg·body weight (bw)). Rats received phytoestrogen-free diet and water ad libitum for 12 weeks. E2 attenuated hyperglycemia, hyperalbuminuria, and hyperaldosteronism in D rats, as well as the diabetes-induced changes in renal protein abundances for the bumetanide-sensitive Na–K–2Cl cotransporter (NKCC2), and the α- and β-subunits of the epithelial sodium channel (ENaC), that is, E2 decreased NKCC2, but increased α- and β-ENaC abundances. In nondiabetic rats, E2 decreased plasma K+ and increased urine K+/Na+ ratio, as well as decreased the abundance of NKCC2, β-ENaC, and α-1-Na–K–adenosine triphosphate (ATP)ase in the outer medulla. Finally, the diabetic, E2 rats had measurably lower final circulating levels of E2 than the nondiabetic E2 rats, despite an identical replacement protocol, suggesting a shorter biological half-life of E2 with diabetes. Therefore, E2 attenuated diabetes and preserved renal sodium handling and related transporter expression levels. In addition, E2 had diabetes-independent effects on renal electrolyte handling and associated proteins. Diabetes mellitus is associated with natriuresis, whereas estrogen has been shown to be renoprotective in diabetic nephropathy and may independently regulate renal sodium reabsorption. The aim of this study was to determine the effects of 17-β estradiol (E2) replacement to diabetic, ovariectomized (OVX) female rats on the expression of major renal sodium transporters. Female, Sprague–Dawley rats (210 g) were randomized into four groups: (1) OVX; (2) OVX+E2; (3) diabetic+ovariectomized (D+OVX); and (4) diabetic+ovariectomized+estrogen (D+OVX+E2). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg·body weight (bw)). Rats received phytoestrogen-free diet and water ad libitum for 12 weeks. E2 attenuated hyperglycemia, hyperalbuminuria, and hyperaldosteronism in D rats, as well as the diabetes-induced changes in renal protein abundances for the bumetanide-sensitive Na–K–2Cl cotransporter (NKCC2), and the α- and β-subunits of the epithelial sodium channel (ENaC), that is, E2 decreased NKCC2, but increased α- and β-ENaC abundances. In nondiabetic rats, E2 decreased plasma K+ and increased urine K+/Na+ ratio, as well as decreased the abundance of NKCC2, β-ENaC, and α-1-Na–K–adenosine triphosphate (ATP)ase in the outer medulla. Finally, the diabetic, E2 rats had measurably lower final circulating levels of E2 than the nondiabetic E2 rats, despite an identical replacement protocol, suggesting a shorter biological half-life of E2 with diabetes. Therefore, E2 attenuated diabetes and preserved renal sodium handling and related transporter expression levels. In addition, E2 had diabetes-independent effects on renal electrolyte handling and associated proteins. Uncontrolled diabetes mellitus (DM) is associated with a natriuresis that, if not renally compensated for, can lead to volume depletion. Previously, we1.Song J. Knepper M.A. Verbalis J.G. et al.Increased renal ENaC subunit and sodium transporter abundances in streptozotocin-induced type 1 diabetes.Am J Physiol Renal Physiol. 2003; 285: F1125-F1137Crossref PubMed Scopus (53) Google Scholar showed an increase in several key distal sodium transport proteins, that is, the bumetanide-sensitive Na–K–2Cl cotransporter (NKCC2), the thiazide-sensitive Na–Cl cotransporter (NCC), and the α-, β-, and γ-subunits of the epithelial sodium channel (ENaC) after only 4 days of streptozotocin-induced type I diabetes in young, male rats. Furthermore, Kim et al.2.Kim D. Sands J.M. Klein J.D. Changes in renal medullary transport proteins during uncontrolled diabetes mellitus in rats.Am J Physiol Renal Physiol. 2003; 285: F303-F309Crossref PubMed Scopus (70) Google Scholar, 3.Klein J.D. Price S.R. Bailey J.L. et al.Glucocorticoids mediate a decrease in AVP-regulated urea transporter in diabetic rat inner medulla.Am J Physiol. 1997; 273: F949-F953PubMed Google Scholar, 4.Kim D. Sands J.M. Klein J.D. Role of vasopressin in diabetes mellitus-induced changes in medullary transport proteins involved in urine concentration in Brattleboro rats.Am J Physiol Renal Physiol. 2004; 286: F760-F766Crossref PubMed Scopus (42) Google Scholar have shown increases in urea transporters, aquaporins, and sodium-coupled cotransporters in more chronic studies (up to 20 days). However, the ability to compensate longer term for type I DM with regard to changes in sodium transporters has not been adequately studied. In addition, we have demonstrated that chronic type II DM in obese Zucker rats results in marked downregulation of the abundance of several key sodium transporters and channel subunits, including the bumetanide-sensitive NKCC2 of the thick ascending limb and the sodium hydrogen exchanger (NHE3).5.Bickel C.A. Knepper M.A. Verbalis J.G. et al.Dysregulation of renal salt and water transport proteins in diabetic Zucker rats.Kidney Int. 2002; 61: 2099-2110Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar This downregulation was most severe in the medullary portion of the kidney and was negatively correlated to creatinine clearance. Recent studies,6.Mankhey R.W. Bhatti F. Maric C. 17beta-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy.Am J Physiol Renal Physiol. 2005; 288: F399-F405Crossref PubMed Scopus (132) Google Scholar, 7.Tofovic S.P. Dubey R.K. Jackson E.K. 2-Hydroxyestradiol attenuates the development of obesity, the metabolic syndrome, and vascular and renal dysfunction in obese ZSF1 rats.J Pharmacol Exp Ther. 2001; 299: 973-977PubMed Google Scholar including our own,6.Mankhey R.W. Bhatti F. Maric C. 17beta-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy.Am J Physiol Renal Physiol. 2005; 288: F399-F405Crossref PubMed Scopus (132) Google Scholar suggest that estrogen and its major metabolites may protect the diabetic kidney from extracellular matrix accumulation, tubulointerstitial fibrosis, glomerulopathy, and nephropathy. This may be partly a result of the ability of estrogen to blunt signaling via the renin–angiotensin–aldosterone system. 17-β Estradiol (E2) replacement to ovariectomized (OVX) rats downregulates angiotensin II type 1 receptor binding in the adrenal gland8.Sandberg K. Ji H. Kidney angiotensin receptors and their role in renal pathophysiology.Semin Nephrol. 2000; 20: 402-416PubMed Google Scholar, 9.Wu Z. Maric C. Roesch D.M. et al.Estrogen regulates adrenal angiotensin AT1 receptors by modulating AT1 receptor translation.Endocrinology. 2003; 144: 3251-3261Crossref PubMed Scopus (76) Google Scholar and aldosterone secretion10.Roesch D.M. Tian Y. Zheng W. et al.Estradiol attenuates angiotensin-induced aldosterone secretion in ovariectomized rats.Endocrinology. 2000; 141: 4629-4636Crossref PubMed Scopus (62) Google Scholar in rats. Nevertheless, E2 replacement to OVX female rats has also been shown to increase the apical plasma membrane residency of NCC, an aldosterone-regulated protein.11.Verlander J.W. Tran T.M. Zhang L. et al.Estradiol enhances thiazide-sensitive NaCl cotransporter density in the apical plasma membrane of the distal convoluted tubule in ovariectomized rats.J Clin Invest. 1998; 101: 1661-1669Crossref PubMed Scopus (119) Google Scholar Therefore, its effects on the renin–angiotensin–aldosterone system, especially with regard to the regulation of renal sodium reabsorptive proteins, are clearly complex. Therefore, in these studies, we sought to determine whether E2 replacement to diabetic OVX female rats would be protective, with regard to the severity of the diabetes itself as well as with regard to regulation of renal sodium balance, and the abundances of the major renal sodium transport proteins. These proteins include (1) the NHE3 of the proximal tubule and thick ascending limb apical membrane, (2) the sodium phosphate cotransporter (NaPi-2), (3) the bumetanide-sensitive NKCC2, (4) the thiazide-sensitive Na–Cl cotransporter (NCC), the (5) α-, (6) β-, and (7) γ-subunits of the ENaC, and (8) the α-1 subunit of the Na–K–ATPase pump. E2 replacement to the diabetic rats normalized bw gain (Figure 1a). There were no significant differences between the OVX, OVX+E2, and the D+OVX+E2 groups, at any of the weeks, except for the final week, where the OVX were significantly heavier than D+OVX+E2. The OVX group was gaining weight at a faster rate, at the end of the study, than either of the E2-replete groups. The D+OVX group was significantly lighter than the other three groups after 5 weeks, at which time the weight of these animals basically plateaued. Individual rat blood glucose levels, at the time of euthanization, are graphed in Figure 1b. E2 replacement to diabetic rats attenuated the hyperglycemia. Several diabetic rats had glucose levels above 28 mmol/l, which were out of range of our glucometer; thus, for statistical purposes, rats were assigned into a category based on their glucose level, that is, (1) normal, <6.7 mmol/l; (2) moderately high, 6.7–16.7; (3) high (but measurable), 16.7–28; and (4) high (out of range), >28. The dashed lines in the figure show how many rats of each treatment fell into each category. Statistical analysis of the category assignations by analysis of variance (ANOVA) on ‘ranks’ or categories revealed that the D+OVX group had significantly higher final blood glucose levels (P<0.05) than the other three groups. Urine volume was increased in diabetic rats, as expected (Figure 2a). However, E2 replacement markedly suppressed this increase, indicative of less osmotic loss of water due to glucosuria. In addition, a reduction in urinary albumin excretion was observed in diabetic rats replaced with E2 (Figure 2b). Estradiol was below the level of detection in most of the OVX rats, as well as in two of six of the D+OVX+E2 rats (Figure 2c). Thus, as with blood glucose, data were categorized into levels 1–4 depending on whether estrogen was (1) undetectable; (2) <73; (3) 73–184; or (4) >184 pmol/l, and ANOVA on ranks was performed. E2 replacement caused a significant increase in the circulating level between OVX and OVX+E2 groups, but not between the D+OVX and D+OVX+E2 groups. Thus, not only did E2 replacement attenuate the diabetes, but also the diabetes seemed to reduce the circulating estradiol levels despite identical replacement protocols. Plasma fructosamine levels were not significantly different between groups, likely due to high variability in the diabetic groups, although there was a trend for them to be higher in the D+OVX group (Table 1). Plasma creatinine levels were reduced by estrogen and urine creatinine was increased in the diabetic rats. However, there were no significant differences in creatinine clearance, an index of glomerular filtration rate, among groups. Urine osmolality, like fructosamine, was highly variable and tended to be decreased, but not significantly different, in the D+OVX group. Plasma arginine vasopressin levels were significantly increased in the diabetic rats, and reduced by E2 replacement.Table 1Renal function and general physiologyaMean±s.e.m.; n=6 for both groups.GroupPlasma fructosamine (μmol/l)Plasma creatinine (μmol/l)Urine creatininebAt 12 weeks. (μmol/day/kg·bw)Creatinine clearancebAt 12 weeks. (ml/min/kg·bw)Urine osmolalitybAt 12 weeks. (mOsm/kg·H2O)Plasma vasopressin (pmol/l)OVX213±7139.1±3.1239±174.36±0.401552±6206.9±0.7OVX+E2215±4522.6±2.6*Significantly different (P<0.05) from OVX.186±325.95±0.791966±7535.6±1D+OVX656±21239.6±5.6267±145.14±0.78348±6717.8±4cSignificantly different from OVX+E2 as determined by one-way ANOVA followed by Tukey's multiple-comparisons test.,*Significantly different (P<0.05) from OVX.D+OVX+E2259±14233.5±3.4250±145.48±0.651113±4427.6±2FactorResults of two-way ANOVA (P-values)Diabetes0.0970.1410.0360.830.380.01Estrogen0.170.0070.10.170.0530.021Interaction0.170.1760.390.360.0890.068ANOVA, analysis of variance; D, diabetic; E2, estrogen; OVX, ovariectomized.Numbers in bold indicate significantly different (P<0.05) P-values for two-way ANOVA.a Mean±s.e.m.; n=6 for both groups.b At 12 weeks.c Significantly different from OVX+E2 as determined by one-way ANOVA followed by Tukey's multiple-comparisons test.* Significantly different (P<0.05) from OVX. Open table in a new tab ANOVA, analysis of variance; D, diabetic; E2, estrogen; OVX, ovariectomized. Numbers in bold indicate significantly different (P<0.05) P-values for two-way ANOVA. Similarly, plasma aldosterone levels were increased significantly (2–3-fold) by diabetes and reduced by E2 (Table 2). However, urinary K+ to Na+ ratio (a putative measure of aldosterone activity) was decreased by diabetes and increased by E2. Renin activity was not different between groups. Plasma sodium levels were decreased significantly by diabetes and returned to near normality by E2. Diabetes, in general, reduced the level of plasma potassium. In addition, in the nondiabetic groups, plasma potassium was significantly reduced by E2 replacement, so that OVX rats had higher levels of plasma K+ than did the other three groups. Finally, fractional excretion of sodium was increased in diabetic rats and this increase was attenuated in E2-treated rats.Table 2Electrolyte regulationaMean±s.e.m.; n=6 for both groups.GroupPlasma aldosterone (nmol/l)Plasma renin activitybGenerated angiotensin I. (ng/ml/h)Urine K+/Na+ ratiocAt 12 weeks.Plasma Na+ (mmol/l)Plasma K+ (mmol/l)Fractional excretion of sodiumcAt 12 weeks.,dCalculated as ((UNa*Pcreat)/(Ucreat*PNa))*100. (%)OVX0.85±0.1672±101.64±0.11140±16.9±0.30.29±0.07OVX+E20.49±0.1370±172.66±0.24*Significantly different (P<0.05) from OVX.140±15.8±0.2*Significantly different (P<0.05) from OVX.0.24±0.06D+OVX2.32±0.43*Significantly different (P<0.05) from OVX.,eSignificantly different from OVX+E2.47±141.49±0.18eSignificantly different from OVX+E2.128±2*Significantly different (P<0.05) from OVX.,eSignificantly different from OVX+E2.5.8±0.1*Significantly different (P<0.05) from OVX.1.36±0.03*Significantly different (P<0.05) from OVX.,eSignificantly different from OVX+E2.D+OVX+E21.09±0.37fSignificantly different from D+OVX as determined by one-way ANOVA followed by Tukey's multiple-comparisons test.53±141.70±0.21eSignificantly different from OVX+E2.137±35.4±0.2*Significantly different (P<0.05) from OVX.0.76±0.03FactorResults of two-way ANOVA (P-values)Diabetes0.0030.310.0040.010.0020.002Estrogen0.0160.540.0080.021<0.0010.15Interaction0.160.450.0450.0680.0750.23ANOVA, analysis of variance; D, diabetic; E2, estrogen; OVX, ovariectomized.Numbers in bold indicate significantly different (P<0.05) P-values for two-way ANOVA.a Mean±s.e.m.; n=6 for both groups.b Generated angiotensin I.c At 12 weeks.d Calculated as ((UNa*Pcreat)/(Ucreat*PNa))*100.* Significantly different (P<0.05) from OVX.e Significantly different from OVX+E2.f Significantly different from D+OVX as determined by one-way ANOVA followed by Tukey's multiple-comparisons test. Open table in a new tab ANOVA, analysis of variance; D, diabetic; E2, estrogen; OVX, ovariectomized. Numbers in bold indicate significantly different (P<0.05) P-values for two-way ANOVA. A summary of all whole-kidney homogenate immunoblots is given in Table 3. Immunoblotting of the whole kidney is carried out to get a general picture of whole-kidney regulation of any particular protein, whereas immunoblotting of the cortex, outer, and inner medulla is carried out to determine whether there may also be regional differences in the regulation of that protein. The cortex, outer and inner medulla blots (when appropriate) are presented in Figures 3, 4, 5 and 6. NHE3 was modestly, but significantly, increased by diabetes in whole kidney (Table 3). In the cortex, the increase in NHE3 was only observed in the D+OVX group (Figure 3a and b). In the outer medulla, there was likewise a trend for diabetes to increase NHE3 (P=0.057, nonsignificant), but there were no differences between individual pairs of means by one-way ANOVA (Figure 3c). NaPi-2 protein in the cortex was significantly decreased by diabetes (Figure 3a and d).Table 3Whole-kidney homogenate immunoblotting band density summary (% OVX)aMean±s.e.m., n=6 for both groups.GroupNHE3NaPi-2NKCC2NCCα-ENaCβ-ENaCγ-ENaC (85 kDa)γ-ENaC (70 kDa)α-1 Na–K–ATPaseOVX100±4100±11100±8100±4100±4100±4100±3100±8100±10OVX+E2111±1*Significantly different (P<0.05) from OVX.64±1986±871±5*Significantly different (P<0.05) from OVX.106±299±7102±586±6101±12D+OVX118±4*Significantly different (P<0.05) from OVX.65±14123±1154±2*Significantly different (P<0.05) from OVX.,bSignificantly different from D+OVX.77±6*Significantly different (P<0.05) from OVX.,bSignificantly different from D+OVX.60±9*Significantly different (P<0.05) from OVX.,bSignificantly different from D+OVX.101±891±6145±22D+OVX+E2122±2*Significantly different (P<0.05) from OVX.63±9118±1451±4*Significantly different (P<0.05) from OVX.,bSignificantly different from D+OVX.105±8cSignificantly different from D+OVX as determined by one-way ANOVA followed by Tukey's multiple-comparisons test.91±6cSignificantly different from D+OVX as determined by one-way ANOVA followed by Tukey's multiple-comparisons test.132±9*Significantly different (P<0.05) from OVX.,bSignificantly different from D+OVX.,cSignificantly different from D+OVX as determined by one-way ANOVA followed by Tukey's multiple-comparisons test.98±13166±16*Significantly different (P<0.05) from OVX.,bSignificantly different from D+OVX.FactorResults of two-way ANOVA (P-values)Diabetes<0.0010.210.017<0.0010.0390.0020.0340.870.003Estrogen0.0140.180.40<0.0010.0060.0420.0190.690.51Interaction0.2110.240.670.0030.0550.0280.0420.260.54ANOVA, analysis of variance; D, diabetic; E2, estrogen; NaPi-2, sodium phosphate cotransporter; NCC, Na–Cl cotransporter; NHE3, sodium hydrogen exchanger; NKCC2, Na–K–2Cl cotransporter; OVX, ovariectomized.Numbers in bold indicate significantly different P-values for two-way ANOVA.a Mean±s.e.m., n=6 for both groups.* Significantly different (P<0.05) from OVX.b Significantly different from D+OVX.c Significantly different from D+OVX as determined by one-way ANOVA followed by Tukey's multiple-comparisons test. Open table in a new tab Figure 4Immunoblotting for the sodium, potassium, two chloride cotransporters (NKCC2), and the sodium, chloride cotransporter (NCC). (a) Example immunoblots for the cortex and outer medulla, probed with polyclonal antibodies against either NKCC2 or NCC, as indicated on the left of the blots. For each blot, lanes are loaded with rats' samples 1–6 from each treatment group, left to right (n=6/group), with an equal amount of total protein loaded in each lane. Coomassie-stained loading gels confirmed equality of loading. (b–d) Corresponding densitometry summaries with two- and one-way P-values provided. Mean band densities plus standard error of measurements for each treatment are plotted. τ indicates a significant (P<0.05) difference from OVX+E2 as determined by one-way ANOVA followed by Tukey's multiple-comparisons test. NKCC2 in the outer medulla was significantly greater in the D+OVX group relative to the OVX+E2 group. Two-way ANOVA of NKCC2 in the outer medulla revealed a significant increase due to diabetes and a significant decrease due to estrogen.View Large Image Figure ViewerDownload (PPT)Figure 5Immunoblotting for the α- and β-subunits of ENaC. (a) Example immunoblots for cortex, outer, and inner medulla, probed with polyclonal antibodies against either α- or β-ENaC, as indicated on the left of the blots. For each blot, lanes are loaded with rats' samples 1–6 from each treatment group, left to right (n=6/group) with an equal amount of total protein loaded in each lane. Coomassie-stained loading gels confirmed equality of loading. (b–g) Corresponding densitometry summaries with two- and one-way P-values provided. Mean band densities plus standard error of measurements for each treatment are plotted. * indicates a significant (P<0.05) difference from OVX and τ from OVX+E2 groups, as determined by one-way ANOVA followed by Tukey's multiple comparisons test. α-ENaC abundance in the cortex was significantly reduced in the D groups relative to the OVX+E2 group. β-ENaC abundance in the cortex was decreased in the D+OVX group relative to OVX+E2. In the outer medulla, β-ENaC was decreased in the OVX+E2 groups relative to OVX group and increased in the D+OVX and D+OVX+E2 groups relative to the OVX+E2 group. In the inner medulla, β-ENaC was increased in the D+OVX group relative to the OVX+E2 group. Two-way ANOVA revealed that diabetes increased β-ENaC in the outer and inner medulla and decreased α-ENaC in the cortex. In addition, estrogen increased β-ENaC in the cortex, but decreased it in the outer medulla.View Large Image Figure ViewerDownload (PPT)Figure 6Immunoblotting for the γ-subunit of ENaC and α-1-Na–K–ATPase. (a) Example immunoblots for the cortex, outer, and inner medulla, probed with antibodies against either γ-ENaC or α-1-Na–K–ATPase, as indicated on the left of the blots. For each blot, lanes are loaded with rats' samples 1–6 from each treatment group, left to right (n=6/group), with an equal amount of total protein loaded in each lane. Coomassie-stained loading gels confirmed equality of loading. (b–g) Corresponding densitometry summaries with two- and one-way P-values provided. Mean band densities plus standard error of measurements for each treatment are plotted. * indicates a significant (P<0.05) difference from OVX, τ from OVX+E2 groups, λ from the D+OVX group, as determined by one-way ANOVA followed by Tukey's multiple-comparisons test. γ-ENaC (85-kDa band) abundance in the cortex was significantly higher in the D+OVX+E2 group relative to OVX. γ-ENaC (85-kDa band) in the outer medulla was increased in the D+OVX+E2 group relative to the OVX+E2 group. α-1-Na–K–ATPase in the cortex was increased in the D+OVX group relative to the OVX group and decreased in the D+OVX+E2 group relative to the D+OVX group. In the outer medulla, α-1-Na–K–ATPase was decreased in the OVX+E2 group relative to the OVX group. Two-way ANOVA revealed that diabetes increased γ-ENaC (85-kDa band) in the outer medulla and α-1-Na–K–ATPase in the cortex. It also decreased α-1-Na–K–ATPase in the outer medulla. Estrogen increased γ-ENaC (85-kDa band) in the cortex.View Large Image Figure ViewerDownload (PPT) ANOVA, analysis of variance; D, diabetic; E2, estrogen; NaPi-2, sodium phosphate cotransporter; NCC, Na–Cl cotransporter; NHE3, sodium hydrogen exchanger; NKCC2, Na–K–2Cl cotransporter; OVX, ovariectomized. Numbers in bold indicate significantly different P-values for two-way ANOVA. In the outer medulla (Figure 4a and c) and in the whole kidney (Table 3), diabetes increased the abundance of the bumetanide-sensitive NKCC2. The outer medullary increase was reduced by E2. The trend was the same in the cortex (Figure 4a and b); however, it did not reach significance. Similarly, the abundance of the thiazide-sensitive NCC was reduced by E2, but only in nondiabetic rats (Table 3, Figure 4a and c). Furthermore, NCC was either unchanged (cortex) or modestly decreased by diabetes (whole kidney). Diabetes reduced both whole-kidney (Table 3) and cortex abundance of the α- as well as the β-subunit of the ENaC (Figure 5a, b, and e). E2 was able to restore the β-subunit to the OVX (nondiabetic) level. Diabetes also modestly reduced the inner and outer medullary abundances of α-ENaC (Figure 5a, c, and d). In contrast, β-ENaC was increased by diabetes in the medulla (Figure 5a, f, and g). Finally, E2 administration to nondiabetic rats resulted in decreased outer medullary β-ENaC abundance (Figure 5a and f) and increased α-ENaC in the cortex (Figure 5a and b). In the cortex and whole-kidney homogenates, of diabetic animals, we found a significant increase in the major band associated with γ-ENaC (85 kDa, Table 3, Figure 6a and b). This band was analyzed separately from the ‘70-kDa band’, due to the fact that these two bands or band regions are differentially regulated.12.Ecelbarger C.A. Kim G.H. Terris J. et al.Vasopressin-mediated regulation of epithelial sodium channel abundance in rat kidney.Am J Physiol Renal Physiol. 2000; 279: F46-F53PubMed Google Scholar, 13.Masilamani S. Kim G.H. Mitchell C. et al.Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney.J Clin Invest. 1999; 104: R19-R23Crossref PubMed Scopus (630) Google Scholar Vasopressin has been shown to increase the density of the 85-kDa band.12.Ecelbarger C.A. Kim G.H. Terris J. et al.Vasopressin-mediated regulation of epithelial sodium channel abundance in rat kidney.Am J Physiol Renal Physiol. 2000; 279: F46-F53PubMed Google Scholar The 70-kDa band is actually a broad series of diffuse bands, the chemical nature of which is not known. This band region has been demonstrated to be increased by aldosterone infusion or feeding of a low-NaCl diet.13.Masilamani S. Kim G.H. Mitchell C. et al.Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney.J Clin Invest. 1999; 104: R19-R23Crossref PubMed Scopus (630) Google Scholar In the outer medulla (Figure 6a and c), E2 replacement to non-D rats resulted in a trend for lower expression of this band (similar to β-ENaC and NKCC2). Cortical (Figure 6a and e) and whole-kidney (Table 3) abundance of α-1-Na–K–ATPase was increased by diabetes. Similar to several other proteins, the outer medullary abundance of α-1-Na–K–ATPase was decreased by E2 (Figure 6a and f). Owing to the high variability in the degree of diabetic severity in the diabetic groups, we also correlated renal protein abundances in the diabetic groups to urinary albumin excretion in the final collection, as a marker of the degree of renal damage (Figure 7). The three proteins in which renal abundance (whole kidney) correlated most closely with albumin excretion are shown. The abundance of NKCC2 showed a significant positive correlation, whereas α- and β-ENaC were significantly negatively correlated to urinary albumin levels. Poorly controlled, DM is associated with a fairly substantial diuresis and natriuresis, as well as, eventually, the development and progression of chronic renal disease. E2 and its analogues have been shown by ourselves6.Mankhey R.W. Bhatti F. Maric C. 17beta-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy.Am J Physiol Renal Physiol. 2005; 288: F399-F405Crossref PubMed Scopus (132) Google Scholar and others14.Gross M.L. Adamczak M. Rabe T. et al.Beneficial effects of estrogens on indices of renal damage in uninephrectomized SHRsp rats.J Am Soc Nephrol. 2004; 15: 348-358Crossref PubMed Scopus (84) Google Scholar, 15.Antus B. Liu S. Yao Y. et al.Effects of progesterone and selective oestrogen receptor modulators on chronic allograft nephropathy in rats.Nephrol Dial Transplant. 2005; 20: 329-335Crossref PubMed Scopus (11) Google Scholar to be protective against the progression of kidney disease. In this report, our major findings included the following: (1) E2 replacement to diabetic rats normalized the abundance of several major renal sodium transport proteins and channel subunits, including the bumetanide-sensitive NKCC2, and the α- and β-subunits of ENaC; (2) E2 replacement to nondiabetic OVX rats independently affected the abundance of several renal sodium transport proteins; in particular, it seemed to reduce the relative abundance of both thick ascending limb- and collecting duct-associated transport or channel proteins in the outer medulla of the kidney; (3) E2 replacement to streptozotocin-induced diabetic female, OVX rats attenuated the severity of the diabetes, as determined by a lessening of hyperglycemia and hyperalbuminuria; and (4) diabetic rats had reduced final circulating levels of estradiol despite a similar replacement protocol for diabetic and nondiabetic, OVX rats. In the remainder of the Discussion, we elaborate on these findings. The administration of E2 to the D rats prevented what appears to be pathologically induced downregulation of select cortical collecting duct proteins, for example, the α- and β-subunits of the ENaC. The pattern of changes for these proteins, with diabetes, is different from what was previously found1.Song J. Knepper M.A. Verbalis J.G. et al.Increased renal ENaC subunit and sodium transporter abundances in streptozotocin-induced type 1 diabetes.Am J Physiol Renal Physiol. 2003; 285: F1125-F1137Crossref PubMed Scopus (53) Google Scholar in the short-term, streptozotocin-treated rats, in which both α- and β-ENaC were increased in abundance after 4–14 days of DM. However, it agreed with the marked downregulation we observed for α-ENaC abundance in obese Zucker rats with chronic, progressive type II diabetes.5.Bickel C.A. Knepper M.A. Verbalis J.G. et al.Dysregulation of renal salt and w" @default.
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