Abstract：
The transmembrane protein SLC22A17 [or the neutrophil gelatinase-associated lipocalin/lipocalin-2 (LCN2)/24p3 receptor] is an atypical member of the SLC22 family of organic anion and cation transporters: it does not carry typical substrates of SLC22 transporters but mediates receptor-mediated endocytosis (RME) of LCN2. One important task of the kidney is the prevention of urinary loss of proteins filtered by the glomerulus by bulk reabsorption of multiple ligands via megalin:cubilin:amnionless-mediated endocytosis in the proximal tubule (PT). Accordingly, overflow, glomerular, or PT damage, as in Fanconi syndrome, results in proteinuria. Strikingly, up to 20% of filtered proteins escape the PT under physiological conditions and are reabsorbed by the distal nephron. The renal distal tubule and collecting duct express SLC22A17, which mediates RME of filtered proteins that evade the PT but with limited capacity to prevent proteinuria under pathological conditions. The kidney also prevents excretion of filtered essential and nonessential transition metals, such as iron or cadmium, respectively, that are largely bound to proteins with high affinity, e.g., LCN2, transferrin, or metallothionein, or low affinity, e.g., microglobulins or albumin. Hence, increased uptake of transition metals may cause nephrotoxicity. Here, we assess the literature on SLC22A17 structure, topology, tissue distribution, regulation, and assumed functions, emphasizing renal SLC22A17, which has relevance for physiology, pathology, and nephrotoxicity due to the accumulation of proteins complexed with transition metals, e.g., cadmium or iron. Other putative renal functions of SLC22A17, such as its contribution to osmotic stress adaptation, protection against urinary tract infection, or renal carcinogenesis, are discussed.
摘要：
跨膜蛋白SLC22A17（或中性粒细胞明胶酶相关脂质运载蛋白（NGAL）/脂质运载蛋白2（LCN2）/24p3受体）是SLC22有机阴离子和阳离子转运蛋白家族的非典型成员：它不携带SLC22转运蛋白的典型底物，但介导LCN2的受体介导的内吞作用（RME）。肾脏的一项重要任务是通过在近端小管（PT）中通过megalin：cubilin：无羊膜介导的RME大量重吸收多种配体来预防肾小球过滤的蛋白质的尿丢失。因此，溢流,肾小球或PT损伤，就像范可尼综合征一样，导致蛋白尿。引人注目的是，在生理条件下，高达20％的过滤蛋白质逸出PT，并被远端肾单位重新吸收。肾脏远端小管和集合管表达SLC22A17，其介导逃避PT的过滤蛋白的RME，但在病理条件下预防蛋白尿的能力有限。肾脏还可以防止过滤的必需和非必需过渡金属（TM）的排泄，如铁（Fe）或镉（Cd），分别,很大程度上与高蛋白质结合，例如脂质运载蛋白-2（LCN2），转铁蛋白,或者金属硫蛋白，或低亲和力，例如微球蛋白或白蛋白。因此，TMs摄取增加可能引起肾毒性。在这里，我们评估了有关SLC22A17结构的文献，拓扑,组织分布,调节和假定的功能，强调肾脏SLC22A17，它与生理学相关，病理学,以及由于与TM复合的蛋白质积累而导致的肾毒性，例如Cd或Fe。SLC22A17的其他推定的肾功能，例如其对渗透应激适应的贡献，防止尿路感染，或肾癌，正在讨论。
