Glomerular and Tubular Function in the Diabetic Kidney

描述(申请人提供)：在过去的十年中，我们提出了肾小球滤过的管状假说，以解释早期糖尿病患者肾功能的几个细微差别。该理论最先应用于糖尿病高滤过，我们已经证明最重要的刺激来自近端小管，在那里早期重吸收的增加通过小管球反馈(TGF)的正常生理作用导致单个肾单位GFR(SNGFR)的增加。早期糖尿病患者近端小管的另一个特征是，它承担了更多的盐平衡责任。近端小管对盐的敏感性是早期糖尿病所谓的“盐悖论”的原因，即近端重吸收的变化与完整的转化生长因子系统相遇，导致饮食盐对GFR的相互影响。糖尿病近端小管对盐的敏感度升高的原因尚不清楚，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，也就是在损伤发生之前很久。我们的目标是更好地了解早期糖尿病肾脏近端高重吸收、肾小球高滤过和肾脏生长的分子机制，假设早期糖尿病诱导的变化对长期结果很重要。在高血糖期间，肾脏可能通过肾小管葡萄糖摄取感觉到高血糖，近端肾小管总重吸收的很大一部分直接或间接与通过SGLT1和SGLT2的钠-葡萄糖共转运有关。这促使我们考虑，在特定目标1中，这些SGLT在早期糖尿病中作为近端重吸收、肾小球滤过和肾脏肥大的控制者，以及在标准的糖尿病肾病小鼠模型中作为进展的效应器。核心方法学将继续是大鼠和小鼠的肾脏清除和显微穿刺术，包括我们手中的缺失SGLT1和SGLT2的基因靶向小鼠。近端重吸收的一个更新的效应物是胰岛素，高血糖素样多肽1(GLP-1)，它作为近端利尿剂具有突出的潜力。GLP-1被DPP-4降解，DPP-4与近端肾小管刷状缘处的GLP-1受体共表达。糖尿病患者GLP-1和DPP-4活性均发生改变。具体目的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的决定因素所起的作用。研究将在药物操作的大鼠、缺乏GLP-1受体的基因操作的小鼠以及移植GLP-1受体缺失的野生型大鼠中使用清除和显微穿刺法。此外，我们将使用特定的药理工具来干扰这一系统，包括DPP-4抑制剂和GLP-1激动剂，这两种药物目前被用于增加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INT信号对肾脏以外的影响，即对血压和盐平衡的影响。 公共卫生相关性：糖尿病对肾脏的影响是阶段性的。糖尿病一开始，肾脏就变大，肾小球滤过率变得异常正常。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症和肾衰竭。糖尿病患者的当代治疗旨在减缓蛋白尿和硬化症发作后进展为肾衰竭的速度。要完全预防糖尿病肾病将是可取的，但要做到这一点，我们首先需要了解肾脏损伤之前的早期事件。有一种由来已久的观点认为，早期的血流动力学表型会导致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，即在出现损伤或硬化之前。

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.