Krishnan Devishree, Pan Wanling, Beggs Megan R, Trepiccione Francesco, Chambrey Régine, Eladari Dominique, Cordat Emmanuelle, Dimke Henrik, Alexander R Todd
Department of Physiology, University of Alberta, Edmonton, AB, Canada.
The Women's and Children's Health Research Institute, Edmonton, AB, Canada.
Front Physiol. 2018 Jan 5;8:1108. doi: 10.3389/fphys.2017.01108. eCollection 2017.
Carbonic anhydrase II (CAII) is expressed along the nephron where it interacts with a number of transport proteins augmenting their activity. Aquaporin-1 (AQP1) interacts with CAII to increase water flux through the water channel. Both CAII and aquaporin-1 are expressed in the thin descending limb (TDL); however, the physiological role of a CAII-AQP1 interaction in this nephron segment is not known. To determine if CAII was required for urinary concentration, we studied water handling in CAII-deficient mice. CAII-deficient mice demonstrate polyuria and polydipsia as well as an alkaline urine and bicarbonaturia, consistent with a type III renal tubular acidosis. Natriuresis and hypercalciuria cause polyuria, however, CAII-deficient mice did not have increased urinary sodium nor calcium excretion. Further examination revealed dilute urine in the CAII-deficient mice. Urinary concentration remained reduced in CAII-deficient mice relative to wild-type animals even after water deprivation. The renal expression and localization by light microscopy of NKCC2 and aquaporin-2 was not altered. However, CAII-deficient mice had increased renal AQP1 expression. CAII associates with and increases water flux through aquaporin-1. Water flux through aquaporin-1 in the TDL of the loop of Henle is essential to the concentration of urine, as this is required to generate a concentrated medullary interstitium. We therefore measured cortical and medullary interstitial concentration in wild-type and CAII-deficient mice. Mice lacking CAII had equivalent cortical interstitial osmolarity to wild-type mice: however, they had reduced medullary interstitial osmolarity. We propose therefore that reduced water flux through aquaporin-1 in the TDL in the absence of CAII prevents the generation of a maximally concentrated medullary interstitium. This, in turn, limits urinary concentration in CAII deficient mice.
碳酸酐酶II（CAII）在整个肾单位中表达，它与多种转运蛋白相互作用以增强其活性。水通道蛋白-1（AQP1）与CAII相互作用，以增加通过水通道的水通量。CAII和水通道蛋白-1均在髓袢降支细段（TDL）中表达；然而，CAII-AQP1相互作用在该肾单位节段中的生理作用尚不清楚。为了确定CAII是否是尿液浓缩所必需的，我们研究了CAII缺陷小鼠的水代谢情况。CAII缺陷小鼠表现出多尿、烦渴以及碱性尿和碳酸氢盐尿，这与III型肾小管酸中毒一致。利钠和高钙尿症会导致多尿，然而，CAII缺陷小鼠的尿钠和钙排泄并未增加。进一步检查发现CAII缺陷小鼠的尿液稀释。即使在禁水后，CAII缺陷小鼠的尿液浓缩能力相对于野生型动物仍然降低。NKCC2和水通道蛋白-2的肾脏表达及光镜定位未改变。然而，CAII缺陷小鼠的肾脏AQP1表达增加。CAII与水通道蛋白-1结合并增加其水通量。髓袢降支细段中通过水通道蛋白-1的水通量对于尿液浓缩至关重要，因为这是产生浓缩髓质间质所必需的。因此，我们测量了野生型和CAII缺陷小鼠的皮质和髓质间质浓度。缺乏CAII的小鼠皮质间质渗透压与野生型小鼠相当：然而，它们的髓质间质渗透压降低。因此，我们提出，在缺乏CAII的情况下，髓袢降支细段中通过水通道蛋白-1的水通量减少，会阻止产生最大程度浓缩的髓质间质。这反过来又限制了CAII缺陷小鼠的尿液浓缩能力。
