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Concentrating Defect in Experimental Nephrotic Syndrome: Altered Expression of Aquaporins and Thick Ascending Limb Na+ Transporters

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Title: Concentrating Defect in Experimental Nephrotic Syndrome: Altered Expression of Aquaporins and Thick Ascending Limb Na+ Transporters
Authors: Fernandez-llama, Patricia; Andrews, Peter; Ecelbarger, Ph.D., Carolyn; Nielsen, Soren; Knepper, Mark
Publisher: Kidney International
Date Published: July 01, 1998
Reference Number: 370
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Abstract • Article • Translation
BACKGROUND: Several pathophysiological states associated with deranged water balance are associated with altered expression and/or intracellular distribution of aquaporin water channels. The possible role of dysregulation of thick ascending limb NaCl transporters, which are responsible for countercurrent multiplication in the kidney, has not been evaluated. METHODS: Semiquantitative immunoblotting and immunocytochemistry were carried out in the kidneys of rat with adriamycin-induced nephrotic syndrome and in vehicle-injected control rats. RESULTS: Preliminary studies confirmed the presence of a severe concentrating defect. Semiquantitative immunoblotting of outer medullary homogenates demonstrated a marked decrease in the abundance of three thick ascending limb Na+ transporters in nephrotic rats, namely the bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1), the type 3 Na/H exchanger (NHE-3), and the alpha 1-subunit of the Na-K-ATPase. These results are predictive of a decrease in the NaCl transport capacity of the medullary thick ascending limb and therefore a decrease in countercurrent multiplication. Immunocytochemistry of outer medullary thin sections demonstrated broad (but highly variable) suppression of BSC-1 expression in the outer medullas of adriamycin-nephrotic rats. There was also a large decrease in outer medullary expression of two collecting duct water channels (aquaporin-2 and -3) and the major water channel of the thin descending limb of Henle's loop (aquaporin-1). CONCLUSION: The concentrating defect in adriamycin-induced nephrotic syndrome in rats is a consequence of multiple defects in water and solute transporter expression, which would alter both the generation of medullary interstitial hypertonicity and osmotic equilibration in the collecting duct. Whether a similar widespread defect in transporter expression is present in idiopathic nephrotic syndrome is, at this point, untested.
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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 nephrons are the main working unit of the kidneys. There are about one million of them in each kidney. Each nephron consists of a filter called a glomerulus, and a tiny tube called the tubule. The tubule is divided into different sections, that nearest the glomerulus is the proximal tubule, that most distant from the glomerulus is the distal tubule. Inbetween these two sections is a section called the loop of Henle. It has a convoluted shape and consists of a thick and thin descending limb and a thick and thin ascending limb.

The majority of the water that flows through the nephrons is reabsorbed by the kidney tissue surrounding the nephrons. The liquid not absorbed is the urine, which is shunted to the bladder and later voided. This water balancing process, essential for human health, is driven by the osmotic process between the tubules and the kidney tissue surrounding it. The loop of Henle plays an important role in generating the proper osmotic conditions between tubule and tissue through the exchange of ions and water.

Some disorders, such as nephrogenic diabetes insipidus (NDI) and nephrotic syndrome upset the process, resulting in deranged water balance. In their study, Fernandez-Llama, et al., injected rats with adriamycin, causing the rats to develop full-blown nephrotic syndrome and its accompanying inability to reabsorb water and concentrate urine.

The authors specifically studied the affected rats' thick ascending limb (TAL) of the loop of Henle, looking to see if there was a reduction of the agents that transport sodium (Na+) from the body water flowing through the TAL to the kidney tissue that surrounds it. If there was such a reduction, it could prevent the necessary osmotic conditions between tubule and tissue from being generated and thus could be a contributing factor in the disorders of the urinary concentrating mechanism experienced by the rats.

The authors found a marked decrease in the number of three separate Na+ transporters occurring in the TAL: BSC-1, NHE-3, and the alpha subunit of the Na-K-ATPase. They also found a large decrease in the expression of two collecting duct water channels: aquaporins-2 and 3. (The tubules connect with and empty into kidney collecting ducts (CDs). These are an essential part of the water reabsorption process. When aquaporins-2 and -3 are significantly decreased in number, the kidneys cannot reabsorb the body water flowing through the CDs.)

How adriamycin-induced nephrotic syndrome causes the decreases of the aquaporins and the Na+ transporters was not addressed in this study. However, the effects of the decreases was evident: an inability to reabsorb water flowing through the CDs, and an inability to generate the osmotic conditions necessary for water absorption from tubules by the kidney tissue.