PDF(Pubmed)
Abstract：
Nicotinamide adenine dinucleotide (NAD) is involved in renal physiology and is synthesized by nicotinamide mononucleotide adenylyltransferase (NMNAT). NMNAT exists as three isoforms, namely, NMNAT1, NMNAT2, and NMNAT3, encoded by Nmnat1, Nmnat2, and Nmnat3, respectively. In diabetic nephropathy (DN), NAD levels decrease, aggravating renal fibrosis. Conversely, sodium-glucose cotransporter-2 inhibitors increase NAD levels, mitigating renal fibrosis. In this regard, renal NAD synthesis has recently gained attention. However, the renal role of Nmnat in DN remains uncertain. Therefore, we investigated the role of Nmnat by establishing genetically engineered mice. Among the three isoforms, NMNAT1 levels were markedly reduced in the proximal tubules (PTs) of db/db mice. We examined the phenotypic changes in PT-specific Nmnat1 conditional knockout (CKO) mice. In CKO mice, Nmnat1 expression in PTs was downregulated when the tubules exhibited albuminuria, peritubular type IV collagen deposition, and mitochondrial ribosome (mitoribosome) excess. In CKO mice, Nmnat1 deficiency-induced mitoribosome excess hindered mitoribosomal translation of mitochondrial inner membrane-associated oxidative phosphorylation complex I (CI), CIII, CIV, and CV proteins and mitoribosomal dysfunction. Furthermore, the expression of hypermethylated in cancer 1, a transcription repressor, was downregulated in CKO mice, causing mitoribosome excess. Nmnat1 overexpression preserved mitoribosomal function, suggesting its protective role in DN.
摘要：
烟酰胺腺嘌呤二核苷酸（NAD）参与肾脏生理，由烟酰胺单核苷酸腺苷酸转移酶（NMNAT）合成。NMNAT以三种亚型存在，即,NMNAT1、NMNAT2和NMNAT3，分别由Nmmat1、Nmmat2和Nmmat3编码。在糖尿病肾病（DN）中，NAD水平下降，加重肾脏纤维化.相反，钠-葡萄糖协同转运蛋白-2抑制剂增加NAD水平，减轻肾脏纤维化。在这方面,肾NAD合成最近受到关注。然而,Nmnat在DN中的肾脏作用仍不确定。因此,我们通过建立基因工程小鼠研究了Nmnat的作用。在三种同工型中，db/db小鼠的近端小管（PT）中的NMNAT1水平显着降低。我们检查了PT特异性Nmnat1条件敲除（CKO）小鼠的表型变化。在CKO小鼠中,当小管显示蛋白尿时，PT中的Nmnat1表达下调，肾小管周围IV型胶原沉积，线粒体核糖体（线粒体）过量。在CKO小鼠中,Nmnat1缺乏诱导的丝裂体过量阻碍线粒体内膜相关氧化磷酸化复合物I（CI）的丝裂体翻译，CIII,CIV,和CV蛋白和线粒体功能障碍。此外，在癌症中表达高甲基化1，一种转录阻遏物，在CKO小鼠中下调，导致线粒体过量。Nmnat1过表达保留丝体功能，提示其在DN中的保护作用。
