Romero Michael F
Departments of Physiology & Biophysics and Pharmacology, Case Western Reserve University School of Medicine, 2119 Abington Road, Cleveland, OH 44106-4970, USA.
Curr Opin Nephrol Hypertens. 2005 Sep;14(5):495-501. doi: 10.1097/01.mnh.0000168333.01831.2c.
Acid-base (H and HCO3) transport in the kidney is crucial for maintaining blood pH, cellular pH and excreting metabolic acid. HCO3 transport in the kidney is mediated by HCO3 transporter proteins which occur in two gene families in humans, vertebrates and invertebrates (SLC4 and SLC26). Since SLC26 transporters have other, non-HCO3 transport functions, this review highlights the history and recent advances in the SLC4 transporters in the kidney. The SLC4 gene and protein family (10 genes) contains three types of HCO3 transporters: Cl-HCO3 exchangers, Na/HCO3 cotransporters and Na-driven Cl-HCO3 exchangers. Function and human chromosomal location have been determined for most members.
Human mutations in AE1 (SLC4A1) and NBCe1 (SLC4A4) are associated with distal and proximal renal tubular acidosis, respectively. Recent advances include the cellular and biophysical mechanisms by which AE1 and NBCe1 mutations lead to renal disease. Mutational and cellular trafficking studies have begun to elucidate the membrane topology and functional domains of AE1 and NBCe1. Knockout mice for AE2 and NBCn1 do not have obvious renal phenotypes. Recently, SLC4A11 (bicarbonate transporter 1) was shown to function as an electrogenic Na/borate cotransporter unable to transport HCO3 but involved in cell cycle control.
SLC4 HCO3 transporters play critical roles in systemic and cellular pH homeostasis. Most of the SLC4 members are present at some level in the kidney. Future studies will likely continue to make use of knockout animals, for example mice and zebrafish, human mutations or polymorphisms to elucidate the normal and pathophysiologic roles of these proteins.
肾脏中的酸碱（H⁺和HCO₃⁻）转运对于维持血液pH值、细胞内pH值以及排泄代谢性酸至关重要。肾脏中的HCO₃⁻转运由HCO₃⁻转运蛋白介导，这些蛋白存在于人类、脊椎动物和无脊椎动物的两个基因家族中（SLC4和SLC26）。由于SLC26转运蛋白具有其他非HCO₃⁻转运功能，本综述重点介绍了肾脏中SLC4转运蛋白的历史和最新进展。SLC4基因和蛋白家族（10个基因）包含三种类型的HCO₃⁻转运蛋白：Cl⁻-HCO₃⁻交换体、Na⁺/HCO₃⁻共转运体和Na⁺驱动的Cl⁻-HCO₃⁻交换体。大多数成员的功能和人类染色体定位已确定。
AE1（SLC4A1）和NBCe1（SLC4A4）的人类突变分别与远端和近端肾小管酸中毒相关。最新进展包括AE1和NBCe1突变导致肾脏疾病的细胞和生物物理机制。突变和细胞转运研究已开始阐明AE1和NBCe1的膜拓扑结构和功能域。AE2和NBCn1基因敲除小鼠没有明显的肾脏表型。最近，SLC4A11（碳酸氢盐转运蛋白1）被证明作为一种电中性Na⁺/硼酸盐共转运体发挥作用，不能转运HCO₃⁻，但参与细胞周期调控。
SLC4 HCO₃⁻转运蛋白在全身和细胞pH稳态中起关键作用。大多数SLC4成员在肾脏中都有一定程度的表达。未来的研究可能会继续利用基因敲除动物，如小鼠和斑马鱼、人类突变或多态性来阐明这些蛋白质的正常和病理生理作用。
