Adeno-associated virus receptor (AAVR) and G protein-coupled receptor 108 (GPR108) (AAVR/GPR108)

Cell-surface entry factors on CLDN16/SLC12A1-positive thick ascending limb cells refers to the molecular machinery, primarily the adeno-associated virus receptor (AAVR, also known as KIAA0319L) and G protein-coupled receptor 108 (GPR108), that facilitates the entry of viral vectors or pathogens into the thick ascending limb (TAL) of the kidney. The TAL is a critical segment of the nephron involved in ion reabsorption and is specifically marked by the expression of Claudin-16 (CLDN16) and the sodium-potassium-chloride cotransporter 2 (NKCC2/SLC12A1). Recent breakthroughs in gene therapy have utilized engineered AAV variants, such as AAV9-JGA, to target these entry factors on TAL cells at the juxtaglomerular apparatus (JGA). This approach allows the vector to bypass the glomerular filtration barrier by accessing the cells directly from the bloodstream via the tubule-afferent arteriole contact. Targeting these factors is being explored for the treatment of inflammatory kidney diseases and genetic tubulopathies like Bartter syndrome or Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC). The interaction involves the binding of the viral capsid to AAVR and GPR108, triggering clathrin-mediated endocytosis and subsequent nuclear delivery of genetic cargo. Additionally, these cells have been studied for the expression of SARS-CoV-2 entry factors like ACE2 and TMPRSS2, although their expression levels in the TAL are generally lower than in the proximal tubule.

Other names

KIAA0319LGPR108AAV entry factorsCell-surface entry factors on TAL cellsAAVRKIAA0319-like protein

Viral capsid binding to cell-surface receptors followed by clathrin-mediated endocytosis and nuclear translocation for transgene delivery.