Aquaporin 11 insufficiency modulates kidney susceptibility to oxidative stress

Abstract

Lawson WE, Gow AJ, Harris RC, Dikov MM, Tchekneva EE. Aquaporin 11 insufficiency modulates kidney susceptibility to oxidative stress. Am J Physiol Renal Physiol 304: F1295-F1307, 2013. First published March 13, 2013 doi:10.1152/ajprenal.00344.2012.-Aquaporin 11 (AQP11) is a newly described member of the protein family of transport channels. AQP11 associates with the endoplasmic reticulum (ER) and is highly expressed in proximal tubular epithelial cells in the kidney. Previously, we identified and characterized a recessive mutation of the highly conserved Cys227 to Ser227 in mouse AQP11 that caused proximal tubule (PT) injury and kidney failure in mutant mice. The current study revealed induction of ER stress, unfolded protein response, and apoptosis as molecular mechanisms of this PT injury. Cys227Ser mutation interfered with maintenance of AQP11 oligomeric structure. AQP11 is abundantly expressed in the S1 PT segment, a site of major renal glucose flux, and Aqp11 mutant mice developed PT-specific mitochondrial injury. Glucose increased AQP11 protein expression in wild-type kidney and upregulation of AQP11 expression by glucose in vitro was prevented by phlorizin, an inhibitor of sodium-dependent glucose transport across PT. Total AQP11 levels in heterozygotes were higher than in wild-type mice but were not further increased in response to glucose. In Aqp11 insufficient PT cells, glucose potentiated increases in reactive oxygen species (ROS) production. ROS production was also elevated in Aqp11 mutation carriers. Phenotypically normal mice heterozygous for the Aqp11 mutation repeatedly treated with glucose showed increased blood urea nitrogen levels that were prevented by the antioxidant sulforaphane or by phlorizin. Our results indicate an important role for AQP11 to prevent glucose-induced oxidative stress in proximal tubules. proximal tubules; acute kidney injury; protein oligomerization.

Transit of H2O2 across the endoplasmic reticulum membrane is not sluggish

“…Accordingly, it is likely that AQPs other than AQP8 play complementary, tissue-and context-specific roles with regard to H 2 O 2 transport at the ER. One obvious candidate is AQP11, the subcellular localization of which is strongly shifted to the ER [45,46]. AQP11 loss-of-function causes destructive symptoms of ER stress, which mainly manifest in the proximal tubular epithelial cells of the kidney [45][46][47] but also in other organs such as the liver [48].…”

“…One obvious candidate is AQP11, the subcellular localization of which is strongly shifted to the ER [45,46]. AQP11 loss-of-function causes destructive symptoms of ER stress, which mainly manifest in the proximal tubular epithelial cells of the kidney [45][46][47] but also in other organs such as the liver [48]. In addition to the tissue-specific expression level of ER AQPs, the H 2 O 2 permeability of the ER membrane is likely regulated by post-translational modifications.…”

Aquaporin 11 variant associates with kidney disease in type 2 diabetic patients

“…In the kidney, AQP11 is exclusively expressed in all PT segments and is regulated by glucose (2,26,37). Our and other studies have demonstrated that in mice, loss of AQP11 function in PTs leads to AKI (26,37) and that AQP11 insufficiency predisposes to hyperglycemia-induced renal dysfunction (2).…”

“…We recently identified aquaporin (AQP)11 haploinsufficiency as a factor predisposing to hyperglycemia-induced nephropathy (2,36). AQPs, primarily water transport proteins, are characterized by the presence of two highly conserved Asn-Pro-Ala (NPA) motifs that, along with the surrounding sequences, are important for pore formation and its functioning (27,28).…”

“…AQP11, with its unusual NH 2 -terminal Asn-Pro-Cys (NPC) motif, which is important for its function, is a member of the novel third group of the AQP superfamily (16,26). AQP11 resides in the endoplasmic reticulum (ER) (26), and previously published data have indicated that AQP11 may maintain ER homeostasis and cytosolic and/or vesicle osmoregulation in the PT (2,20,29,45).…”