A Novel AQP2 Sequence Variant Causing Aquaporin-2 Retention in the Cytoplasm and Autosomal Dominant Nephrogenic Diabetes Insipidus

Hinrichs, Gitte Rye; Baltzer, Sandrine; Pallien, Tamara; Svenningsen, Per; Dalgaard, Emil B.; Hertz, Jens Michael; Bistrup, Claus; Jensen, Boye L.; Klussmann, Enno

doi:10.1016/j.ekir.2022.07.001

Cited by 3 publications

(3 citation statements)

References 9 publications

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Section: Discussionmentioning

confidence: 99%

“…Zhang et al have found that AQP11 was down-regulated in DR and resulted in intracellular edema in DR subsequently (Zhang et al, 2022). AQP2 was also reported to be involved in diabetic kidney diseases (Hadidi et al, 2022; Hinrichs et al, 2022). However, to our knowledge, it was the first time that AQP1 was reported to be involved in physiological as well as pathological vascular lumen formation.…”

Section: Discussionmentioning

confidence: 99%

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Aquaporins enriched in endothelial vacuole membrane regulate the diameters of microvasculature in hyperglycemia

Chen

Qin

et al. 2023

Preprint

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In patients with diabetic microvascular complications, reduced vessel perfusion or vascular occlusion is a common characteristic which will cause the insufficient blood supply. However, identification of novel regulators involved in microvascular lumenization defects is hindered by the lacking of a model for imaging the blood vessels at high resolution in vivo. Taking advantage of the transparency of zebrafish, we observed the reduction of vascular diameter and compromised perfusion in high glucose treated embryos. RNA sequencing and whole-mount in situ hybridization analysis indicated that two aquaporins (aqp1a.1 and aqp8a.1) were significant down-regulated, which was further confirmed by endothelial specific Q-PCR. It was also shown that the two aqps were spatio-temporally enriched in the endothelial cells (ECs) of vascular system. Zebrafish with loss of aqp1a.1 or aqp8a.1 displayed lumenization defects in intersegmental vessels, recapitulating the phenotype in hyperglycemic zebrafish model. While overexpressing the aquaporins in zebrafish promoted the enlargement of the vascular diameter. Moreover, the defective vasculature induced by high-glucose treatment could be rescued by aqp1a.1 upregulation. In addition, both aqp1a.1 and apq8a.1 were localized in the intracellular vacuoles in cultured ECs as well as in the ECs of sprouting ISVs, and loss of Aqps caused the reduction of those vacuoles, which was required for lumenization. Finally, we found that the expression of human AQP1 was downregulated in diabetic human retina samples and high-glucose treated human retinal microvascular endothelial cells. All these results suggest that EC-enriched aquaporins have a role in developmental and pathological blood vessel lumenization, and they might be potential targets for gene therapy to cure diabetes-related vascular lumenization defects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Aquaporins enriched in endothelial vacuole membrane regulate the diameters of microvasculature in hyperglycemia

Chen

Qin

et al. 2023

Preprint

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“…The X‐linked inheritance is more apparent in males due to the lack of a second X chromosome. In 10% of the cases, NDI is caused by mutations in the AQP2 gene (Hinrichs et al., 2022).…”

Section: Introductionmentioning

confidence: 99%

Many kinases for controlling the water channel aquaporin‐2

Kharin

Klussmann

2023

The Journal of Physiology

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Aquaporin‐2 (AQP2) is a member of the aquaporin water channel family. In the kidney, AQP2 is expressed in collecting duct principal cells where it facilitates water reabsorption in response to antidiuretic hormone (arginine vasopressin, AVP). AVP induces the redistribution of AQP2 from intracellular vesicles and its incorporation into the plasma membrane. The plasma membrane insertion of AQP2 represents the crucial step in AVP‐mediated water reabsorption. Dysregulation of the system preventing the AQP2 plasma membrane insertion causes diabetes insipidus (DI), a disease characterised by an impaired urine concentrating ability and polydipsia. There is no satisfactory treatment of DI available. This review discusses kinases that control the localisation of AQP2 and points out potential kinase‐directed targets for the treatment of DI. image

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Aquaporins enriched in endothelial vacuole membrane regulate the diameters of microvasculature in hyperglycaemia

Chen,

Qin,

et al. 2024

Cardiovascular Research

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Background In patients with diabetic microvascular complications, decreased perfusion or vascular occlusion, caused by reduced vascular diameter, is a common characteristic that will lead to insufficient blood supply. Yet, the regulatory mechanism and effective treatment approach remain elusive. Methods and Results Our initial findings revealed a notable decrease in the expression of human AQP1 in both diabetic human retina samples (49 healthy vs. 54 diabetic samples) and high-glucose-treated human retinal microvascular endothelial cells. Subsequently, our investigations unveiled a reduction in vascular diameter and compromised perfusion within zebrafish embryos subjected to high glucose treatment. Further analysis indicated a significant downregulation of two aquaporins, aqp1a.1 and aqp8a.1, which are highly enriched in ECs and are notably responsive to hyperglycemic conditions. Intriguingly, the loss of function of aqp1a.1 and/or aqp8a.1 resulted in a reduction of intersegmental vessel diameters, effectively mirroring the phenotype observed in the hyperglycemic zebrafish model. The overexpression of aqp1a.1/aqp8a.1 in zebrafish ECs led to notable enlargement of microvascular diameters. Moreover, the reduced vessel diameters resulting from high-glucose treatment were effectively rescued by the overexpression of these aquaporins. Additionally, both aqp1a.1 and apq8a.1 were localized in the intracellular vacuoles in cultured ECs as well as the ECs of sprouting ISVs, and the loss of Aqps caused the reduction of those vacuoles, which was required for lumenization. Notably, while the loss of AQP1 did not impact EC differentiation from human stem cells, it significantly inhibited vascular formation in differentiated ECs. Conclusion EC-enriched aquaporins regulate the diameter of blood vessels through an intracellular vacuole-mediated process under hyperglycemic conditions. These findings collectively suggest that aquaporins expressed in ECs hold significant promise as potential targets for gene therapy aimed at addressing vascular perfusion defects associated with diabetes.

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A Novel AQP2 Sequence Variant Causing Aquaporin-2 Retention in the Cytoplasm and Autosomal Dominant Nephrogenic Diabetes Insipidus

Cited by 3 publications

References 9 publications

Aquaporins enriched in endothelial vacuole membrane regulate the diameters of microvasculature in hyperglycemia

Aquaporins enriched in endothelial vacuole membrane regulate the diameters of microvasculature in hyperglycemia

Many kinases for controlling the water channel aquaporin‐2

Aquaporins enriched in endothelial vacuole membrane regulate the diameters of microvasculature in hyperglycaemia

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