Glomerular and Tubular Function in the Diabetic Kidney

描述（由申请人提供）：在过去的十年中，我们提出了肾小球滤过的肾小管假说，以解释早期糖尿病肾功能的几个细微差别。该理论首先应用于糖尿病超滤，我们已经证明，压倒一切的刺激来自近端小管，其中早期重吸收的增加通过正常的肾小管肾小球反馈（TGF）生理作用导致单个肾单位GFR（SNGFR）升高。糖尿病早期近端小管的另一个特征是它承担了增加的盐平衡责任。近端小管的这种盐敏感性是早期糖尿病中所谓的“盐悖论”的原因，其中近端重吸收的变化遇到完整的TGF系统，导致膳食盐对GFR的相互作用。是什么使糖尿病患者近曲小管对盐的敏感性增高尚不清楚，尽管肥大本身似乎与此有关。这项研究的重点将继续放在糖尿病早期肾脏发生的事件上，早在损伤发生之前。我们的目的是更好地了解参与近端重吸收，肾小球超滤和肾脏生长在早期糖尿病肾脏的分子机制，假设早期糖尿病引起的变化是重要的长期结果。在高血糖症期间，肾脏可能通过肾小管葡萄糖摄取感知高血糖症，并且总体近端肾小管重吸收的大部分直接或间接与通过SGLT 1和SGLT 2的钠-葡萄糖共转运相关。这促使我们在具体目标1中考虑这些SGLT作为早期糖尿病近端重吸收、肾小球滤过和肾脏肥大的控制者以及作为糖尿病肾病标准小鼠模型进展的效应物的作用。核心方法将继续是大鼠和小鼠的肾脏清除和显微穿刺，包括我们手头上缺乏SGLT 1和SGLT 2的基因靶向小鼠。近端重吸收的一种更新颖的效应物是肠促胰岛素，胰高血糖素样肽1（GLP-1），其作为近端利尿剂具有突出的潜力。GLP-1被脱肽酶4（DPP-4）降解，DPP-4与GLP-1受体在近端肾小管刷状缘共表达。GLP-1和DPP-4活性在糖尿病中均发生改变。具体目标2旨在了解GLP-1 / GLP-1受体系统和DPP-4作为近端重吸收和肾小球滤过决定因素的作用。研究将在GLP-1操作大鼠、缺乏GLP-1受体的遗传操作小鼠和移植有GLP-1受体缺失肾的野生型小鼠中采用清除和微穿刺。此外，我们将使用特定的药理学工具来干扰这一系统，包括DPP-4抑制剂和GLP-1激动剂，这些药物目前用于增加2型糖尿病患者的胰岛素分泌。具体目标3是确定肾脏SGLT和肾脏以外肠促胰岛素信号传导的影响，即对血压和盐平衡的影响。 公共卫生相关性：糖尿病影响肾脏的阶段。在糖尿病的发病初期，肾脏变大，GFR变得超正常。最近对糖尿病肾脏的基础和临床研究侧重于多年后发生的硬化和肾衰竭。糖尿病患者的现代管理旨在减缓蛋白尿和硬化发作后向肾衰竭的进展。为了预防糖尿病肾病的发生，我们首先需要了解肾损伤发生前的早期事件。长期以来，人们认为早期血液动力学表型引起糖尿病肾脏的随后死亡。这项研究的重点是糖尿病的早期阶段，在有损伤或硬化之前。

DESCRIPTION (provided by applicant): Over the past decade, we have developed a tubular hypothesis of glomerular filtration to account for several nuances of kidney function in early diabetes. The theory was first applied to diabetic hyperfiltration and we have demonstrated that the overriding stimulus comes from the proximal tubule where an early increase in reabsorption leads to a rise in single nephron GFR (SNGFR) through the normal physiologic actions of tubuloglomerular feedback (TGF). Another feature of the proximal tubule in early diabetes is that it assumes increased responsibility for salt balance. This salt sensitivity of the proximal tubule is responsible for the so-called "salt paradox" in early diabetes where changes in proximal reabsorption encounter an intact TGF system leading to a reciprocal effect of dietary salt on GFR. What confers heightened salt-sensitivity on the diabetic proximal tubule is unknown, although hypertrophy, per se, seems to be involved. The focus of this research will continue to be on events that befall the kidney early in diabetes, long before injury develops. We aim to better understand the molecular mechanisms involved in proximal hyperreabsorption, glomerular hyperfiltration and kidney growth in the early diabetic kidney with the assumption that early diabetes-induced changes are important for the long-term outcome. During hyperglycemia, the kidney may sense hyperglycemia via tubular glucose uptake and a high fraction of overall proximal tubular reabsorption is linked, directly or indirectly, to sodium-glucose co-transport via SGLT1 andSGLT2. This prompted us to consider in, Specific Aim 1, the role of these SGLTs as controllers of proximal reabsorption, glomerular filtration, and kidney hypertrophy in early diabetes and as effectors of progression in a standard mouse model of diabetic nephropathy. The core methodology will continue to be renal clearance and micropuncture in the rat and mouse, including gene-targeted mice lacking SGLT1 and SGLT2,which we have in hand. A more novel effector of proximal reabsorption is the incretin, glucagon-like peptide 1(GLP-1), which has outstanding potential as a proximal diuretic. GLP-1 is degraded by the depeptidyl peptidase 4(DPP-4), which is co-expressed with the GLP-1 receptor in proximal tubular brush border. Both GLP-1 and DPP-4activity are altered in diabetes. Specific Aim 2 is designed to understand the role of the GLP-1 / GLP-1 receptor system and DPP-4 as determinants of proximal reabsorption and glomerular filtration. Studies will employ clearance and micropuncture in the pharmacologically manipulated rats , genetically manipulated mice lacking the GLP-1 receptor, and wild type transplanted with GLP-1 receptor null kidneys. In addition we will use specific pharmacological tools to perturb this system, including DPP-4 inhibitors and GLP-1 agonists, which are currently used to augment insulin secretion in patients with type 2 diabetes. Specific Aim 3 is to determine impacts of renal SGLT and incretin signaling beyond the kidney, namely on blood pressure and salt balance. PUBLIC HEALTH RELEVANCE: Diabetes affects the kidney in stages. At the very onset of diabetes, the kidney grows large and GFR becomes supranormal. Recent basic and clinical research on the diabetic kidney is weighted toward sclerosis and kidney failure that occur many years later. The contemporary management of patients with diabetes is aimed toward slowing the progression to kidney failure after the onset of proteinuria and sclerosis. To prevent diabetic nephropathy altogether would be preferable, but to accomplish this we first need to understand earlier events that antedate renal injury. There is a longstanding idea that the early hemodynamic phenotype provokes the subsequent demise of a diabetic kidney. This research focuses on that early stage of diabetes, before there is injury or sclerosis.