Renal Sodium Transport in the Obese Zucker Rat

肥胖 Zucker 大鼠的肾钠转运

• 批准号: 7340799
• 负责人: Carolyn Mary Ecelbarger
• 金额: $ 2.33万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340799
• 关键词: Acute; Age; Agonist; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Autoradiography; Binding; Blood Pressure; Canrenone; Carrier Proteins; Collagen Type IV; Data; Diabetes Mellitus; Diet; Disease model; Distal; Down-Regulation; Enalapril; Endocrine; Enzymes; Epithelial; Equilibrium; Etiology; Fibronectins; Glucocorticoids; Goals; Homeostasis; Hormones; Hyperinsulinism; Hypertension; Hypertrophy; In Situ; In Situ Hybridization; In Vitro; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; Kidney; Kidney Diseases; Laboratories; Location; Messenger RNA; Mineralocorticoid Receptor; Mineralocorticoids; Modeling; Molecular; Na(+)-K(+)-Exchanging ATPase; Natriuresis; Obesity; PPAR gamma; Partner in relationship; Pathology; Pattern; Phosphorylation; Plasma; Play; Process; Protein Tyrosine Kinase; Proteins; Range; Rattus; Receptor Signaling; Regulation; Relative (related person); Renal Hypertension; Renal tubule structure; Renin; Renin-Angiotensin-Aldosterone System; Research Personnel; Role; Series; Signal Transduction; Signaling Protein; Sodium; Sodium Channel; Sodium Chloride; Steroids; System; Testing; Up-Regulation; Vasopressins; Water; Week; Zucker Rats; age related; aged; blood pressure regulation; candesartan; day; design; dietary restriction; epithelial Na+ channel; mRNA Expression; prevent; programs; protein expression; receptor; receptor binding; receptor expression; response; rosiglitazone; saluretic; thiazide; water channel

Obesity and insulin resistance are associated with hypertension. Inappropriate retention of sodium by the kidney is likely to play a major role. We previously showed that the obese Zucker rat (a model for these disorders) have increased renal protein abundance for three major sodium transport proteins: the alpha-1 subunit of Na-K-ATPase, the thiazide-sensitive NaCI cotransporter (NCC or TSC) and the beta-subunit of the epithelial sodium channel (ENaC). In contrast, as, they aged, obese rats developed renal hypertrophy along with diabetes and had a relative decrease in many important salt and water transport proteins, as compared to age-matched controls. We suggest that dysregulation of several important hormone systems in sodium balance may play a role in both alterations in sodium transport protein expression, as well as, the rapid develop of nephropathy. Candidate systems include the renin-angiotensin-aldosterone system (RAAS) and insulin (and or insulin resistance). We hypothesize that dysregulation of major sodium transport proteins of the kidney in the obese Zucker rat with age, is due at least in part to increased RAAS activity, and hyperinsulinemia, which in combination, result in inappropriate sodium retention and elevated blood pressure. Our specific aims include: 1) to determine if angiotensin II ATla receptor expression, binding, and activity is upregulated in the obese Zucker rat and whether this upregulation plays a role in changes in renal sodium transporter regulation, blood pressure, and renal hypertrophy; 2) to determine if enhanced mineratocorticoid receptor (MR) activity plays a role in increased whole kidney protein abundance of the thiazide-sensitive NaCI cotransporter (NCC), blood pressure, and renal hypertrophy, in the obese Zucker rat; 3) to determine the cellular location and sensitivity of the renal insulin receptor in obese Zucker rats relative to lean age-mates; 4) to determine whether treatment of insulin resistance with a PPAR-gamma agonist will decrease relative renal protein abundance of NCC, beta-ENaC, and Na-K-ATPase, as well as reduce blood pressure and renal hypertrophy in the obese Zucker rat, and whether these effects are reversed with short- term insulin infusion. These studies will allow us to determine the importance of each of these potential regulatory hormone systems in dyregulation of sodium transporter expression, sodium balance, and blood pressure in these obese rats.

肥胖和胰岛素抵抗与高血压有关。钠的不适当保留 肾可能起主要作用。我们先前表明，肥胖的Zucker大鼠（这些模型） 疾病）增加了三种主要钠转运蛋白的肾蛋白丰度：α-1 Na-K-ATP酶的β-亚基、噻嗪敏感性NaCl协同转运蛋白（NCC或TSC）和 上皮钠通道（ENaC）。相反，随着年龄的增长，肥胖大鼠沿着肾脏肥大 与糖尿病患者相比， 年龄匹配的对照组。我们认为，在钠离子缺乏的情况下， 平衡可能在钠转运蛋白表达的改变中起作用， 发展为肾病。候选系统包括肾素-血管紧张素-醛固酮系统（RAAS）和 胰岛素（或胰岛素抵抗）。我们推测，主要的钠转运蛋白的失调， 肥胖Zucker大鼠的肾脏随年龄增长，至少部分是由于RAAS活性增加， 高胰岛素血症，其组合导致不适当钠潴留和升高的血液 压力我们的具体目标包括：1）确定血管紧张素II AT 1a受体的表达、结合和 活动在肥胖Zucker大鼠中上调，以及这种上调是否在肾功能的变化中起作用， 钠转运蛋白调节、血压和肾肥大; 2）确定是否增强 盐皮质激素受体（MR）活性在增加全肾蛋白丰度中起作用， 肥胖Zucker大鼠中噻嗪敏感性NaCl协同转运蛋白（NCC）、血压和肾脏肥大; 3)确定肥胖Zucker大鼠肾脏胰岛素受体的细胞定位和敏感性 4）确定用PPAR-gamma激动剂治疗胰岛素抵抗是否会 降低NCC、beta-ENaC和Na-K-ATP酶的相对肾蛋白丰度，以及降低血液 压力和肾脏肥大的肥胖Zucker大鼠，以及这些影响是否被逆转与短- 长期胰岛素输注。这些研究将使我们能够确定这些潜力中的每一个的重要性 钠转运蛋白表达、钠平衡和血液调节异常中的调节激素系统 肥胖大鼠体内的压力

项目成果

Sex and body-type interactions in the regulation of renal sodium transporter levels, urinary excretion, and activity in lean and obese Zucker rats.

• DOI: 10.1016/s1550-8579(06)80219-6
• 发表时间: 2006-12-01
• 期刊: Gender medicine
• 作者: Riazi, Shahla;Madala-Halagappa, Veerendra K;Ecelbarger, Carolyn A
• 通讯作者: Ecelbarger, Carolyn A

Sex and age result in differential regulation of the renal thiazide-sensitive NaCl cotransporter and the epithelial sodium channel in angiotensin II-infused mice.

性别和年龄导致血管紧张素 II 输注小鼠肾噻嗪类敏感 NaCl 协同转运蛋白和上皮钠通道的差异调节。

• DOI: 10.1159/000252776
• 发表时间: 2009
• 期刊: American journal of nephrology
• 影响因子: 4.2
• 作者: Tiwari,Swasti;Li,Lijun;Riazi,Shahla;Halagappa,VeerendraKMadala;Ecelbarger,CarolynM
• 通讯作者: Ecelbarger,CarolynM

Chronic rosiglitazone therapy normalizes expression of ACE1, SCD1 and other genes in the kidney of obese Zucker rats as determined by microarray analysis.

通过微阵列分析确定，长期罗格列酮治疗可使肥胖 Zucker 大鼠肾脏中 ACE1、SCD1 和其他基因的表达正常化。

• DOI: 10.1055/s-2008-1042429
• 发表时间: 2008
• 期刊: Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association
• 作者: Song,J;Liu,H;Ressom,HW;Tiwari,S;Ecelbarger,CM
• 通讯作者: Ecelbarger,CM

Time course of AQP-2 and ENaC regulation in the kidney in response to PPAR agonists associated with marked edema in rats.

• DOI: 10.1016/j.phrs.2008.03.013
• 发表时间: 2008-05
• 期刊: Pharmacological research
• 影响因子: 9.3
• 作者: Swasti Tiwari;E. Blasi;J. Heyen;A. Mcharg;C. Ecelbarger

Sex differences in renal nitric oxide synthase, NAD(P)H oxidase, and blood pressure in obese Zucker rats.

肥胖 Zucker 大鼠肾一氧化氮合酶、NAD(P)H 氧化酶和血压的性别差异。

• DOI: 10.1016/s1550-8579(07)80042-8
• 发表时间: 2007
• 期刊: Gender medicine. official journal of the Partnership for Gender-Specific Medicine at Columbia University
• 作者: Riazi,Shahla;Madala-Halagappa,VeerendraK;Dantas,AnaPaula;Hu,Xinqun;Ecelbarger,CarolynA
• 通讯作者: Ecelbarger,CarolynA