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Editorials |
Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland
Correspondence: Dr. Thomas L. Pallone, Division of Nephrology, N3W143, 22 S. Greene Street, UMMS, Baltimore, MD 21201. Phone: 410-328-5720; Fax: 410-328-5685; E-mail: tpallone{at}medicine.umaryland.edu
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Introduction |
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Aquaporins and urea transporters have been identified, and isoform-specific antibodies have been generated to study their distributions.9,10 Computing power and software for digitizing serial tissue sections has been combined with immunostaining for nephron- and vascular-specific epitopes to clarify many unknown features and create impressive three-dimensional reconstructions that defy full presentation in two-dimensional journal pages.8,11 This detail has provided groundwork for increasingly sophisticated mathematical models that replace primitive notions of a well-mixed interstitium with localized exchanges between nephrons and vessels.4,6 Methods for measurement of transport properties of vessels and nephrons have not improved in parallel and paucity of such knowledge remains a brake on the interpretation of this otherwise impressive array of molecular and computational advancements.
In the above context, Zhai et al. provide us with an important revision concerning the distribution of aquaporin 1 (AQP1) and the UT-A2 urea carrier in the outer medulla.12 Murine immunochemistry shows that AQP1 expression is below detection in 90% of thin descending limbs of short looped nephrons (SLN-DTL) with type 1 epithelium. In contrast, SLN-DTL with type 2 epithelia and long-looped nephrons (LLN-DTL) outside vascular bundles express AQP1. SLN-DTL expressed the UT-A2 urea transporter over the last 28% to 44% of their length preceding transition to the thick ascending limb, whereas LLN-DTL do not. This pattern of AQP1 expression conflicts somewhat with prior descriptions, but the current effort was tailored by accomplished investigators to address the issue at hand. Moreover, previously known AQP1 expression in adjacent descending vasa recta (DVR) was readily verified by their methods. The polyclonal anti-AQP1 antibody, under scrutiny, targets a sequence of 19 amino acids within the carboxy terminus and has been successfully used by many investigators. Masking of epitopes in SLN-DTL relative to adjacent DVR is not an inviting explanation for the result, and so we are encouraged to accept the finding.
The inner stripe of the outer medulla is separated into vascular bundles and the interbundle region. In rodents, the SLN-DTL migrates to the bundle periphery where it flows co-current and countercurrent to descending vasa recta and ascending vasa recta, respectively. In the bundle center, only descending vasa recta lie adjacent to ascending vasa recta so that countercurrent urea recycling to the inner medulla is readily inferred. Ascending vasa recta returning via the vascular bundle periphery are associated with both descending vasa recta and SLN-DTL, and it is interesting that each expresses a facilitated urea carrier, UT-B and UT-A2, respectively.10,13 Some fraction of the ascending vasa recta urea load presumably enters the SLN-DTL to be directed to the thick ascending limb, distal tubule, and collecting ducts. The relative fraction of ascending vasa recta urea that diffuses to descending vasa recta versus SLN-DTL depends upon the conductances imparted by their paracellular pathways and respective urea transporters. Rigorous prediction of net urea fluxes within vascular bundles will require knowledge of red blood cell, vasa recta and SLN-DTL permeabilities and solute reflection coefficients, flow rates, geometry, an appropriate system of differential equations, and a computer.
Apart from UT-B and UT-A2 expression, we can ask why descending vasa recta in vascular bundles and LLN-DTL in the interbundle region express another common transporter, AQP1. The explanation may lie in a similar need to reduce luminal flows before penetration of the deep medulla. To that end, a transmural gradient favoring osmotic withdrawal of water is generated by the lag in equilibration of descending vasa recta plasma and interstitium. A transmural osmotic gradient may also exist across the LLN-DTL because of adjacent thick ascending limbs that absorb NaCl and raise vicinal osmolality. In either case, AQP1 is expressed to efficiently shunt water out of the structure to venous blood and renal cortex. By slowing flow in descending vasa rectae and LLN-DTL, the efficiency of diffusional exchange is enhanced in the deep inner medulla where interstitial gradients are most steep, the last bit of water is extracted from the collecting duct, and interstitial solute "washout" must be minimized. Mathematical simulations have predicted that AQP1 expression may increase papillary interstitial osmolality by that mechanism.14,15
The majority of nephrons give rise to SLN-DTL, not LLN-DTL. Their luminal water content does not reach the inner medulla. Instead, it is directed to the thick ascending limb before the inner-outer medullary junction and largely reabsorbed by AQP2-expressing cortical segments. Stated simply, the lack of need to remove water from the SLN-DTL lumen in the outer medulla may account for omission of AQP1 expression.
A few words of interpretational caution are in order. Most importantly, immunochemistry cannot fully predict transport properties. The SLN-DTL is notoriously difficult to isolate and study by in vitro microperfusion. Assuming its correct identification in hamsters, osmotic water permeability was found to be high.16 Lack of AQP1 expression also does not predict the characteristics of parallel transport pathways; for example, paracellular water transport might be driven by osmotic or hydraulic pressure gradients. The pars recta has been variably described to actively secrete urea.10,17 If that truly occurs, and the rate is sufficiently high, an unlikely possibility is that the transepithelial urea gradient across the SLN-DTL favors export rather than uptake of urea via UT-A2 in the inner stripe. Finally, AQP1 may conduct nitric oxide.18 One might hypothesize that transendothelial water transport is a bystander of no importance and that transport of nitric oxide is the primary role of AQP1 in vascular bundles. In that case it might serve to control exposure of pericytes in descending vasa recta to nitric oxide and direct nitric oxide from outside vascular bundles to react with its sink, the hemoglobin in red blood cells.
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Acknowledgments |
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Footnotes |
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See related article, "Aquaporin-1 Is not Expressed in Descending Thin Limbs of Short Loop Nephrons," on pages 2937–2944.
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