Role of the SLC22A17/lipocalin-2 receptor in renal endocytosis of proteins/metalloproteins: a focus on iron- and cadmium-binding proteins

Am J Physiol Renal Physiol. 2023 Nov 1;325(5):F564-F577. doi: 10.1152/ajprenal.00020.2023. Epub 2023 Aug 17.

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.

Keywords: hemoglobin; metallothionein; transferrin; α1-microglobulin; β2-microglobulin.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadmium / metabolism
  • Endocytosis
  • Humans
  • Iron / metabolism
  • Kidney Tubules, Proximal / metabolism
  • Lipocalin-2 / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-2 / metabolism
  • Metalloproteins* / metabolism
  • Metallothionein / metabolism
  • Nephrosis* / metabolism
  • Organic Cation Transport Proteins / metabolism
  • Proteinuria / metabolism

Substances

  • Lipocalin-2
  • Metalloproteins
  • Cadmium
  • Iron
  • Metallothionein
  • Low Density Lipoprotein Receptor-Related Protein-2
  • SLC22A17 protein, human
  • Organic Cation Transport Proteins