Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Department of Internal Medicine, Tokyo Dental College Ichikawa General Hospital, Chiba 272-8583, Japan.
Cell Rep. 2019 Apr 2;27(1):199-212.e5. doi: 10.1016/j.celrep.2019.03.024.
Nicotinamide adenine dinucleotide (NAD) metabolism plays a critical role in kidneys. We previously reported that decreased secretion of a NAD precursor, nicotinamide mononucleotide (NMN), from proximal tubules (PTs) can trigger diabetic albuminuria. In the present study, we investigated the role of NMN-producing enzyme nicotinamide phosphoribosyltransferase (Nampt) in diabetic nephropathy. The expression of Nampt in PTs was downregulated in streptozotocin (STZ)-treated diabetic mice when they exhibited albuminuria. This albuminuria was ameliorated in PT-specific Nampt-overexpressing transgenic (TG) mice. PT-specific Nampt-conditional knockout (Nampt CKO) mice exhibited TBM thickening and collagen deposition, which were associated with the upregulation of the profibrogenic gene TIMP-1. Nampt CKO mice also exhibited the downregulation of sirtuins, particularly in Sirt6. PT-specific Sirt6-knockout mice exhibited enhanced fibrotic phenotype resembling that of Nampt CKO mice with increased Timp1 expression. In conclusion, the Nampt-Sirt6 axis in PTs serves as a key player in fibrogenic extracellular matrix remodeling in diabetic nephropathy.
烟酰胺腺嘌呤二核苷酸 (NAD) 代谢在肾脏中起着关键作用。我们之前曾报道过，近端小管 (PT) 中 NAD 前体烟酰胺单核苷酸 (NMN) 的分泌减少会引发糖尿病白蛋白尿。在本研究中，我们研究了 NAD 产生酶烟酰胺磷酸核糖基转移酶 (Nampt) 在糖尿病肾病中的作用。当 STZ 处理的糖尿病小鼠出现白蛋白尿时，PT 中 Nampt 的表达下调。PT 特异性 Nampt 过表达转基因 (TG) 小鼠的这种白蛋白尿得到改善。PT 特异性 Nampt 条件性敲除 (Nampt CKO) 小鼠表现出 TBM 增厚和胶原沉积，这与促纤维化基因 TIMP-1 的上调有关。Nampt CKO 小鼠还表现出沉默调节蛋白，特别是 Sirt6 的下调。PT 特异性 Sirt6 敲除小鼠表现出增强的纤维化表型，类似于 Nampt CKO 小鼠，Timp1 表达增加。总之，PT 中的 Nampt-Sirt6 轴是糖尿病肾病中纤维性细胞外基质重塑的关键因素。
