MD, PhD, FAHA, Professor of Physiology, Director, The Robert and Mary Cade Laboratory, BMSB 662A, Box 26901, Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, 940 S. L. Young Boulevard, Oklahoma City, OK 73126-0901.
Endocrinology. 2013 Oct;154(10):3855-63. doi: 10.1210/en.2013-1053. Epub 2013 Aug 8.
Klotho is a recently discovered anti-aging gene and is primarily expressed in kidneys. In humans, the klotho level decreases with age whereas the prevalence of chronic kidney disease (CKD) increases with age. Diabetic nephropathy is the most common form of CKD, which leads to end-stage renal disease. A decrease in klotho has been found in kidneys of patients with diabetic nephropathy. The purpose of this study is to assess whether klotho gene deficiency affects early diabetic nephropathy in a mouse of model of type 1 diabetes induced by streptozotocin (STZ). Male KL(+/-) mutant and wild-type mice (6-8 weeks) were injected with multiple low doses of STZ. Renal functions and renal blood flow were assessed. Kidneys were collected for histological examination and molecular assays of TGFβ1 and mammalian targets of rapamycin (mTOR) signaling. Klotho deficiency in KL(+/-) mutant mice exacerbated STZ-induced increases in urine albumin, blood urea nitrogen, expansion of mesangial matrix in renal glomeruli, and kidney hypertrophy, suggesting a protective role of klotho in kidney function and structure. Klotho deficiency did not affect renal blood flow. Notably, klotho deficiency significantly increased phosphorylation of Smad2, indicating enhanced TGFβ1 signaling in kidneys. Klotho deficiency also increased phosphorylation of mTOR and S6 (a downstream effector of mTOR), indicating enhanced mTOR signaling in kidneys of early diabetic mice. Thus, klotho gene deficiency may make kidneys more susceptible to diabetic injury. Klotho gene deficiency exacerbated early diabetic nephropathy via enhancing both TGFβ1 and mTOR signaling in kidneys.
Klotho 是一种新发现的抗衰老基因，主要在肾脏中表达。在人类中，klotho 水平随年龄增长而降低，而慢性肾脏病（CKD）的患病率随年龄增长而增加。糖尿病肾病是最常见的 CKD 形式，可导致终末期肾病。在糖尿病肾病患者的肾脏中发现 klotho 减少。本研究旨在评估 klotho 基因缺失是否会影响由链脲佐菌素（STZ）诱导的 1 型糖尿病小鼠模型中的早期糖尿病肾病。雄性 KL(+/-)突变体和野生型小鼠（6-8 周）接受多次低剂量 STZ 注射。评估肾功能和肾血流量。收集肾脏进行组织学检查和 TGFβ1 和哺乳动物雷帕霉素靶蛋白（mTOR）信号的分子分析。KL(+/-)突变体小鼠中 klotho 的缺失加剧了 STZ 诱导的尿白蛋白、血尿素氮增加、肾小球系膜基质扩张和肾脏肥大，表明 klotho 在肾功能和结构中具有保护作用。klotho 的缺失不影响肾血流量。值得注意的是，klotho 的缺失显著增加了 Smad2 的磷酸化，表明肾脏中 TGFβ1 信号增强。klotho 的缺失还增加了 mTOR 和 S6（mTOR 的下游效应物）的磷酸化，表明早期糖尿病小鼠肾脏中 mTOR 信号增强。因此，klotho 基因缺失可能使肾脏更容易受到糖尿病损伤。klotho 基因缺失通过增强肾脏中的 TGFβ1 和 mTOR 信号加重了早期糖尿病肾病。
