Genetic Restoration of Aldose Reductase to the Collecting Tubules Restores Maturation of the Urine Concentrating Mechanism

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Title: Genetic Restoration of Aldose Reductase to the Collecting Tubules Restores Maturation of the Urine Concentrating Mechanism
Authors: Yang, James Y.; Tam, W. Y.; Tam, Sidney C.F.; Guo, Hong; Wu, Xiachun; Li, Guohua; Chau, Jenny F. L.; Klein, MD, PhD, Janet; Chung, Sookja K.; Sands, Jeff M.; Chung, Stephen S.M.
Publisher: American Journal of Physiology: Renal Physiology
Date Published: July 01, 2006
Reference Number: 706
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To investigate the underlying causes for aldose reductase deficiency-induced diabetes insipidus, we carried out studies with three genotypic groups of mice. These included wild-type mice, knockout mice, and a newly created bitransgenic line that was homozygous for both the aldose reductase null mutation and an aldose reductase knockin transgene driven by the kidney-specific cadherin promoter to direct transgene expression in the collecting tubule epithelial cells. We found that from early renal developmental stages onward, urine osmolality did not exceed 1,000 mosmol/kgH2O in aldose reductase-deficient mice. The functional defects were correlated with significant renal cellular and structural abnormalities that included cell shrinkage, apoptosis, disorganized tubular and vascular structures, and segmental atrophy. In contrast, the transgenic aldose reductase expression in the bitransgenic mice largely but incompletely rescued urine concentrating capacity and significantly improved renal cell survival, cellular morphology, and renal structures. Together, these results suggest that aldose reductase not only plays important roles in osmoregulation and medullary cell survival but may also be essential for the full maturation of the urine concentrating mechanism.
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

The majority of research into the causes of congenital nephrogenic diabetes insipidus (NDI) has focused on the pivotal role played by mutations in the vasopressin 2 receptor gene and the aquaporin 2 (AQP2) gene. However, recent research indicates that among the many other proteins that play a vital part in the kidney’s ability to concentrate urine, a pivotal one is aldose reductase (AR). AR is found throughout the body. In the kidney, AR catalyzes the conversion of glucose to sorbitol. This is important because sorbitol plays a vital role in the osmotic process in the kidney. It is through osmosis that the kidney reabsorbs bodily water. This results in concentrated urine.

Yang, et al., were one of the research teams that established the centrality of AR in urine concentration. In this study, they sought to clarify the mechanisms through which AR deficiency leads to excessive urination and thirst, two of the main clinical symptoms of NDI. To determine whether an AR deficiency in the kidney is sufficient to cause NDI, and to determine the role of AR in maturing the ability to concentrate urine, the research team studied three groups of mice:

  1. Normal mice (WT);
  2. Mice bred to be missing the AR gene and thus be incapable of synthesizing AR (KO); and
  3. Mice bred to carry both the AR null mutation gene and an AR knock in transgene (BT).

The WT served as the control group. The KO served as models of what happens in the kidney without AR. The BT, because they carry both a gene that negates AR and one that expresses a kidney specific AR transgene, could serve to show, if the data supported it, that a local kidney deficiency is sufficient to cause NDI. This is because the BT mice would not have AR anywhere in their body except the kidney (unlike normal mice who have it body wide). So, if the BT mice had normal or near normal kidney urine concentration, it would indicate the necessity of AR for that function.

The researchers found that the KO mice never developed the ability to concentrate urine, and their kidneys had numerous structural abnormalities. BT mice urine concentrating ability gradually started increasing at 3 weeks of age, and it began functioning on a more improved level at 5 weeks. The WT mice matured their ability at 3 weeks. Showing that AQP2 and V2R levels were normal in all three groups of mice, the researchers felt their data strongly indicates that AR is essential for the full maturation of the kidney’s ability to concentrate urine and for proper kidney cellular structure.