Renal transport proteins in excreted urine: Gold mine or gold dust?
Authors: Peter Gross
Journal: Kidney International (2004)

A decade ago, the Sasaki laboratory from Tokyo demonstrated the regular occurrence of aquaporin-2 (AQP-2) water channel in excreted urine of patients1Kanno K. Sasaki S. Hirata Y. et al.Urinary excretion of aquaporin-2 in patients with diabetes insipidus.N Engl J Med. 1995; 332: 1540-1545Crossref PubMed Scopus (269) Google Scholar. Its excretion rate appeared to correlate with the plasma vasopressin (VP) concentration1Kanno K. Sasaki S. Hirata Y. et al.Urinary excretion of aquaporin-2 in patients with diabetes insipidus.N Engl J Med. 1995; 332: 1540-1545Crossref PubMed Scopus (269) Google Scholar. In the present issue of Kidney International, Funayama et al2Funayama H. Nakamura T. Saito T. et al.Urinary excretion of aquaporin-2 water channel exaggerated dependent upon vasopressin in congestive heart failure.Kidney Int. 2004; 66: 1387-1392Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar from Saitama report urinary AQP-2 excretion rates in 65 patients suffering cardiac failure (CF). The authors find increased VP and increased urinary AQP-2, and they conclude that the latter depends on the former2Funayama H. Nakamura T. Saito T. et al.Urinary excretion of aquaporin-2 water channel exaggerated dependent upon vasopressin in congestive heart failure.Kidney Int. 2004; 66: 1387-1392Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar. Anything new or dÉja vue? The present data2Funayama H. Nakamura T. Saito T. et al.Urinary excretion of aquaporin-2 water channel exaggerated dependent upon vasopressin in congestive heart failure.Kidney Int. 2004; 66: 1387-1392Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar are intriguing. First, the relationship between AQP-2 and VP turns out to be less straightforward than expected. For example, although urinary AQP-2 and VP were unquestionably related in a general sense, one detail of the study shows a decrease of AQP-2 when the simultaneous VP increased by approximately 100% (group IV vs. III) (Figs. 1A and 2). Conceivably, this discrepancy could be due to: the clinical nature of the New York Heart Association (NYHA) classification; inherent variations of VP within short periods of time in a given patient; and the very high VP in the group IV and III patients alike probably causing near complete V2 receptor occupancy in both. But there may be more reasons. According to the literature3Wen H. Frokiaer J. Kwon T.-H. Nielsen S. Urinary excretion of aquaporin-2 in rat is mediated by a vasopressin-dependent apical pathway.J Am Soc Nephrol. 1999; 10: 1416-1429PubMed Google Scholar, it is possible that the urinary AQP-2 excretion rate is more a reflection of the actual abundance of AQP-2 in the apical cell membrane of collecting duct principal cells (CD-PC) rather than one of related VP. This would be interesting. If confirmed in patients it would imply that urinary AQP-2 is a superior measure of actual CD water permeability, and one that clinicians have at their disposal. Another consideration is that the V2 receptor–mediated signalling is subject to cellular modification [e.g., 4Tamma G. Wiesner B. Furkert J. et al.The prostaglandin E2 analogue sulprostone antagonizes vasopressin-induced antidiuresis through activation of Rho.J Cell Sci. 2003; 116: 3285-3294Crossref PubMed Scopus (91) Google Scholar]. Therefore, measuring “the final common pathway” in the form of urinary AQP-2 may provide more of a close-up picture of the action than measuring VP. Both aspects of reasoning, therefore, suggest that more should be done to substantiate (or discredit) this new potential paradigm. Perhaps simultaneous measurements of free water clearance, urinary AQP-2 (and VP) could serve towards these ends. At a time when V2-VP antagonists are hitting the clinician's doorstep5Gerbes A.L. Gülberg V. GINÈS P. et al.Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: A randomized double-blind multicenter trial.Gastroenterol. 2003; 124: 933-939Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar, improved tools in the “water trade” would seem to be no small fry. The foregoing speculations bring up a second point: How does AQP-2 get into the tubular fluid? Very little research has been reported. It appears that neither sloughing of CD cells nor shedding of cell membrane are involved1Kanno K. Sasaki S. Hirata Y. et al.Urinary excretion of aquaporin-2 in patients with diabetes insipidus.N Engl J Med. 1995; 332: 1540-1545Crossref PubMed Scopus (269) Google Scholar. Hypothetically, retrieval of AQP-2 from CD-PC apical membrane into multivesicular bodies (MVB) may be the mechanism. It could lead to packaging of undegradated AQP-2 into endosomes, followed by their exocytic fusion with the cell membrane, and release of undegradated AQP-2 into the tubular fluid6Théry C. Zitvogel L. Amigorena S. Exosomes: Composition, biogenesis and function.Nature Reviews. 2002; 2: 569-579Google Scholar,7Stoorvogel W. Kleijmeer M.J. Geuze H.J. Raposo G. The biogenesis and functions of exosomes.Traffic. 2002; 3: 321-330Crossref PubMed Scopus (651) Google Scholar, since the endosomal pathway serves to bypass lysosomes in the case of proteins that are difficult to degradate7Stoorvogel W. Kleijmeer M.J. Geuze H.J. Raposo G. The biogenesis and functions of exosomes.Traffic. 2002; 3: 321-330Crossref PubMed Scopus (651) Google Scholar. However, there is no specific data directly reporting AQP-2, MVB, and endosomes. Conceivably, basic research using cultured cells [e.g., 8Storm R. Klussmann E. Geelhaar A. et al.Osmolality and solute composition are strong regulators of AQP 2 expression in renal principal cells.Am J Physiol Renal Physiol. 2003; 284: F189-F198Crossref PubMed Scopus (66) Google Scholar] might help to shed light on these issues. A clear understanding of the pathway(s) of “transfer” of AQP-2 from cell to tubular fluid shall be paramount. Why? Because interpretations of urinary AQP-2 will eventually depend on whether its “transfer” from cell membrane to urine occurs in some tightly regulated manner or is chaotic. My bias is that only in the former scenario will the stake begin to resemble a veritable goldmine, as opposed to a barren land with some gold dust. And then there is yet another twist. Knepper et al from Bethesda, Maryland, published evidence showing the presence of all major apical renal tubular salt transporters in excreted urine [e.g., 9]. The implicit suggestion was that if the urinary excretion rates were measured they would correspond to the transporters' abundance in the kidney10Knepper M.A. Proteomics and the kidney.J Am Soc Nephrol. 2002; 13: 1398-1408Crossref PubMed Scopus (108) Google Scholar. The resemblance of this situation—and its open questions—to our foregoing discussion of AQP-2 is obvious. Here9Mckee J.A. Kumar S. Ecelbarger C.A. et al.Detection of Na+ transporter proteins in urine.J Am Soc Nephrol. 2000; 11: 2128-2132PubMed Google Scholar, the goldmine would shine even more blindingly because of nuggets in there supposedly labelled “Gitelman syndrome,”“protein rescue,”“ADPKD-I,”“renal transplantation,” etc. However, for now we must remain with our feet firmly on the ground. We first have to do the homework. We must clarify the mode of “transfer” of apical membrane proteins into the tubular fluid. The article by Funayama et al2Funayama H. Nakamura T. Saito T. et al.Urinary excretion of aquaporin-2 water channel exaggerated dependent upon vasopressin in congestive heart failure.Kidney Int. 2004; 66: 1387-1392Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar in the present issue of Kidney International is stimulating in several ways, including this one. Stay tuned!