Ion channels – Membrane Transport – Integrative Physiology
Kidney International (1998) 54, 170–179; doi:10.1046/j.1523-1755.1998.00984.x
Concentrating defect in experimental nephrotic syndrome: Altered expression of aquaporins and thick ascending limb Na+ transporters
Patricia Fernández-Llama, Peter Andrews, Carolyn A Ecelbarger, Søren Nielsen and Mark A Knepper
Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, and Department of Cell Biology, Georgetown University School of Medicine, Washington, D.C.,; Department of Cell Biology, Institute of Anatomy, University of Aarhus, Aarhus, Denmark
Correspondence: Mark A. Knepper, M.D., Ph.D., National Institutes of Health, Bldg 10, Room 260, 10 Center Drive MSC 1603, Bethesda, Maryland 20892-1603, USA. E-mail: knep@helix.nih.gov
Received 6 October 1997; Revised 17 February 1998; Accepted 17 February 1998.
Abstract
Concentrating defect in experimental nephrotic syndrome: Altered expression of aquaporins and thick ascending limb Na+ transporters.
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 
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 in humans is, at this point, untested.
Keywords:
Na-K-2Cl cotransporter, NHE-3, Na-K-ATPase, adriamycin, aquaporin water channels, TAL, nephrotic syndrome, hypertonicity, transport osmotic equilibration
