Molecular Insights into the Pathogenesis of Inherited Renal Tubular Disorders
| Title: | Molecular Insights into the Pathogenesis of Inherited Renal Tubular Disorders |
|---|---|
| Author: | Guay-Woodford, MD, Lisa M. |
| Publisher: | Current Opinion in Nephrology and Hypertension |
| Date Published: | March 01, 1995 |
| Reference Number: | 75 |
Physiologic and biochemical studies have suggested that the inherited disorders cystinuria, Liddle's syndrome, and perhaps Bartter syndrome all result from defects in renal tubular transport processes. With the recent isolation of several candidate transporter genes, these clinically based hypotheses have begun to be confirmed at a molecular level. In addition, the cloning of the water-channel family of proteins has facilitated the characterization of a second gene defect in congenital nephrogenic diabetes insipidus. This review integrates the pathophysiology of these inherited renal tubular disorders with recent molecular genetic discoveries, and provides a starting point for unraveling their pathogenesis at the molecular level.
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)
For instance, through analysis of inheritance patterns of the kidney disorder, nephrogenic diabetes insipidus (NDI), the disease location was placed on the long arm of the X chromosome. NDI is characterized by the kidney's insensitivity to the antidiuretic hormone, arginine vasopressin (AVP). This results in the inability of the kidney to reabsorb water, concentrate urine and balance body water. Normally, AVP binds with a specific receptor, the vasopressin-2 receptor (V2R), to initiate the molecular sequence which results in urine concentration and water reabsorption in the kidney collecting duct. The V2R gene is located on the same area of the X-chromosome where NDI was mapped based on inheritance patterns. Since V2R is essential to the urine concentrating process it was the most likely candidate as the molecular cause of NDI inherited in the X-linked mode. And when defective V2Rs from mutated V2R genes were tested in laboratory cell cultures, researchers discovered that the V2Rs were incapable of performing their function, which is to bind with AVP. If V2Rs cannot bind with AVP then the molecular sequence which results in urine concentration cannot happen. Thus, mutated V2R genes were discovered to be a cause of NDI.
In addition, researchers mapped another inheritance pattern associated with NDI. This much rarer form of NDI was inherited in an autosomal recessive trait. (Autosomal chromosomes are non-sex chromosomes; X and Y chromosomes are sex hormones.) Since the pattern indicated another chromosome than the X chromosome, another candidate gene had to be found.
The water-transporting protein, aquaporin-2, (AQP2) is the final link in the molecular sequence leading to urine concentration initiated when AVP binds with V2R. When signaled by the AVP, it inserts itself in the apex of the principal cells of the kidney collecting duct, making them able to let much more water pass through them than usual. This is how the kidney is able to reabsorb water flowing through the kidney collecting ducts and concentrate urine. When signaled, the AQP2s then shuttle out of the cell membrane back into their holding place inside the cell.
Researchers analyzed the AQP2 genes of NDI patients with the autosomal recessive mode of inheritance and found they were mutated. The researchers tested the functional capacities of the AQP2s synthesized by the mutated AQP2 genes and found they were unable to perform their function of making cell membranes more water permeable. Thus, it was found that mutated AQP2 genes were the molecular basis of this form of NDI. Both forms of NDI have identical symptoms even though their molecular bases differs.