Aquaporin 11 deletion results in induceable proximal tubule injury in response to metabolic challenge

Aquaporin 11 (AQP11) is a channel protein with unknown biological function expressed intracellularly in multiple tissues, among others in kidney proximal tubule epithelium. The neonate Aqp11 gene knockout (KO) mice show injury of the proximal tubule (PT) cells, manifesting as dilatation of RER cisterns, leading to apoptosis of the PT epithelial cells (Morishita et al, Mol Cell Biol. 2005). The mice develop cortical cysts within the first weeks of life and die due to kidney failure. It is unclear if the kidney failure is caused by functional insufficiency of the PT in the absence of AQP11, or by the abnormal development of the nephron and resulting structural malformation of the kidney. We have developed an inducible Aqp11 KO mouse model, where we can temporally control the time point of Aqp11 gene disruption by injection of tamoxifen. We performed microscopic analyses of the PT morphology after induction of AQP11 mutation in unchallenged mice and after different metabolic challenges (fasting/re‐feeding, administration of free amino acids). In mice where AQP11 deletion was induced after the completion of kidney development we observe no cellular damage of PT cells and no cyst formation for up to 4 months after disruption of the Aqp11 gene. When the mice are metabolically stressed (fasting/re‐feeding, administration of free amino acids) the PT cells suffer acute injury with development of giant vacuoles, similar to those observed in neonatal total AQP11 KO mice. In conclusion, we propose that AQP11 function is necessary for proper PT cell function during states of increased protein/amino acid supply, such as during the neonatal period, when mice feed on protein‐rich milk, and in adults subject to high amino acid metabolism challenge. We hypothesize that continuous PT injury during neonatal period results in abnormal development of more distal tubule segments and cyst formation, possibly by impairment of fluid flow in the tubule.