Defective water and glycerol transport in the proximal tubules of AQP7 knockout mice

Abstract

water channel is known as a member of the aquaglyceroporins, which facilitate the transport of glycerol as well as water. Although AQP7 is abundantly expressed on the apical membrane of the proximal straight tubules in the kidney, the physiological role of AQP7 is still unknown. To investigate this, we generated AQP7 knockout mice. The water permeability of the proximal tubule brush-border membrane measured by the stopped-flow method was slightly but significantly reduced in the AQP7 knockout mice compared with that of wild-type mice (AQP7, 18.0 Ϯ 0.4 ϫ 10 Ϫ3 cm/s vs. wild-type, 20.0 Ϯ 0.3 ϫ 10 Ϫ3 cm/s). Although AQP7 solo-knockout mice did not exhibit a urinary concentrating defect, AQP1/AQP7 double-knockout mice had a reduction in urinary concentrating ability compared with AQP1 soloknockout mice, suggesting that the amount of water reabsorbed through AQP7 in the proximal straight tubules is physiologically substantial. On the other hand, AQP7 knockout mice showed marked glyceroluria (AQP7, 1.7 Ϯ 0.34 mg/ml vs. wild-type, 0.005 Ϯ 0.002 mg/ml). This identified a novel glycerol reabsorption pathway in the proximal straight tubules. In two mouse models of proximal straight tubule injury, the cisplatin-induced acute renal failure (ARF) model and the ischemic ARF model, an increase in urine glycerol was observed (pretreatment, 0.007 Ϯ 0.005 mg/ml; cisplatin, 0.063 Ϯ 0.043 mg/ml; ischemia, 0.076 Ϯ 0.02 mg/ml), suggesting that urine glycerol could be used as a new biomarker for detecting proximal straight tubule injury.

Homozygosity for aquaporin 7 G264V in three unrelated children with hyperglyceroluria and a mild platelet secretion defect

“…A pronounced loss of glycerol in the urine coincident with normal plasma concentration values has never been described in humans, although AQP7-deficient mice have been shown to have hyperglyceroluria. 19 Renal AQP7 is responsible for reabsorption of glycerol at the renal proximal tubules in coordination with AQP3. 30,31 All the homozygous carriers of G264V AQP7 in our study had hyperglyceroluria, whereas no glycerol loss was present in the heterozygous parents.…”

Cardiac aquaporin expression in humans, rats, and mice

“…Furthermore, there was no evidence of upregulation of AQP-4 expression in the rat over the observation period after ischemia. Physiologically relevant AQP function can be difficult to distinguish in an in vitro analysis in some cases (43). On the other hand, the presence alone of an AQP does not provide evidence for physiological relevance, borne out by investigations of AQP-4 in skeletal muscle function (54).…”

Mouse model of inducible nephrogenic diabetes insipidus produced by floxed aquaporin-2 gene deletion

“…The NDI in AQP1 null mice is due to a combination of defective near-isosmolar fluid absorption in the proximal tubule (31) and defective countercurrent multiplication produced by reduced water permeability in thin descending limb of Henle (3) and outer medullary descending vasa recta (27). Mice lacking AQP7, which is expressed only in the S3 segment of the proximal tubule, have little if any defect in urinary concentrating ability (32). AQP3 null mice, which have reduced water permeability in collecting duct basolateral membrane, also manifest NDI with low urine osmolality (260 mosmol/kgH 2 O) and moderate polyuria (8 ml/day), but with partial vasopressin sensitivity (17).…”