Impaired Aquaporin and Urea Transporter Expression in Rats with Adriamycin-Induced Nephrotic Syndrome

Title: Impaired Aquaporin and Urea Transporter Expression in Rats with Adriamycin-Induced Nephrotic Syndrome
Authors: Fernandez-llama, Patricia; Andrews, Peter; Nielsen, Soren; Ecelbarger, Ph.D., Carolyn; Knepper, Mark
Publisher: Kidney International
Date Published: May 01, 1998
Reference Number: 372
Nephrotic syndrome is associated with abnormal regulation of renal water excretion. To investigate the role of collecting duct water channels and solute transporters in this process, we have carried out semiquantitative immunoblotting of kidney tissues from rats with adriamycin-induced nephrotic syndrome. These experiments demonstrated that adriamycin-induced nephrotic syndrome is associated with marked decreases in expression of aquaporin-2, aquaporin-3, aquaporin-4, and the vasopressin-regulated urea transporter in renal inner medulla, indicative of a suppression of the capacity for water and urea absorption by the inner medullary collecting duct. In contrast, expression of the alpha(1)-subunit of the Na,K-ATPase in the inner medulla was unaltered. Light and electron microscopy of perfusion-fixed kidneys demonstrated that the collecting ducts are morphologically normal and unobstructed. Inner medullary expression of the descending limb water channel, aquaporin-1, was not significantly altered, pointing to a selective effect on the collecting duct. Aquaporin-2 and aquaporin-3 expression was also markedly diminished in the renal cortex, indicating that the effect is not limited to the inner medullary collecting duct. Differential centrifugation studies and immunocytochemistry in inner medullary thin sections demonstrated increased targeting of aquaporin-2 to the plasma membrane, consistent with the expected short-term action of vasopressin on aquaporin-2 trafficking. The extensive down-regulation of aquaporin and urea transporter expression may represent an appropriate renal response to the extracellular volume expansion observed in nephrotic syndrome, but may occur at the expense of decreased urinary concentrating and diluting capacity.
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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.
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The kidneys regulate the body's salt and water balance. They accomplish this by the osmotic exchange of water and solutes (such as salt and urea) that takes place between the nephrons and the kidney tissue that surrounds them. The nephrons are the main working unit of the kidney. Each consists of a filter called a glomerulus and a tiny tube called a tubule. The tubule empties into a kidney collecting duct (CD).

The osmotic exchange between the tubule and collecting duct on one side, and the tissue that surrounds them (the interstitium) on the other, is made possible by a variety of molecular structures called transporters in the tubules and CDs that allow the water and solutes to travel between the tissues and tubules/CDs. Aquaporins (AQPs) are a type of water transporter, some types of which are located in the CD. They are integral membrane proteins that increase the water permeability (Pf) of the apical membranes of the principal cells of the CDs, thus allowing water flowing through the kidney CD to be reabsorbed by the kidney tissue surrounding it. Three AQPs, AQP 2, 3 and 4 are located in the kidney CDs. The vasopressin-regulated urea transporter (VRUT) is an example of a solute transporter. It is located in the CD and helps urea cross the membranes separating the CD and the interstitium.

Some diseases are associated with abnormal regulation of salt and water by the kidneys which results in imbalanced body water problems. Nephrotic syndrome, a disease of the kidney tubules, is one of them. In their earlier work, Fernandez-Llama et al., had examined the number of water and solute transporters expressed by rats induced with nephrotic syndrome by an injection of puromycin aminonucleoside (PAN). They found these rats experienced a marked decrease in the number of AQP2 and AQP3 in a section of the collecting duct called the inner medullary CD (IMCD). The authors wanted to see if the decrease of AQPs experienced by rats with PAN-induced nephrotic syndrome was unique to the PAN model or a more general characteristic of the nephrotic syndrome.

They injected rats with adriamycin, and the rats developed full blown nephrotic syndrome. Then the authors examined the rats' tubules and CDs to determine if there was an altered expression of CD water and solute transporters that they could associate with adriamycin-induced nephrotic syndrome. The authors discovered that there was a marked decrease in the expression of all three of the aquaporins located in the CD: AQP2, AQP3 and AQP4. AQP2 and AQP3 were also down-regulated in PAN-induced nephrotic syndrome, and the authors concluded that such down-regulation is a feature of nephrotic syndrome in general rather than being the result of any of the substances used to cause nephrotic syndrome.

The authors also checked the expression of AQPs 2 and 3 in the cortex of the CD of the adriamycin-injected mice and found reduced numbers there as well. This suggested that there is a general decrease in AQPs 2 and 3 throughout the CD system in adriamycin-induced nephrotic system. The authors also found that the urea transporter, VRUT, located in the IMCD, was also greatly reduced in numbers. VRUT is important to the urinary concentrating mechanism, thus its suppression may contribute to the concentrating defect seen in nephrotic syndrome. The number of most of the other major proteins in the IMCD were not reduced, so the down-regulation of transporter protein expression appears to be relatively selective.

Fernandez-Llama, et al., speculate that the extensive down-regulation of AQPs and VRUT in the CD may be the kidneys' way of trying to balance the fluid retention that is part of nephrotic syndrome. That is, the reduction in numbers of these transporters diminishes the amount of water that can be reabsorbed by the kidney and this water is voided as dilute urine. This response entails a decrease in urinary concentrating and diluting capacity on the part of the kidney, limiting its ability to maintain water balance.