Combet S, Gouraud S, Gobin R, Berthonaud V, Geelen G, Corman B, Verbavatz J-M
CEA, Institut de Biologie et Technologies de Saclay and CNRS URA 2096, Orsay, France.
Am J Physiol Renal Physiol. 2008 Jun;294(6):F1408-14. doi: 10.1152/ajprenal.00437.2007. Epub 2008 Mar 26.
Aging kidney is associated in humans and rodents with polyuria and reduced urine concentrating ability. In senescent female WAG/Rij rats, this defect is independent of arginine-vasopressin (AVP)/V(2) receptor/cAMP pathway. It has been attributed to underexpression and mistargeting of aquaporin-2 (AQP2) water channel in the inner medullary collecting duct (IMCD). We showed previously that dDAVP administration could partially correct this defect. Since AQP2 can also be regulated by AVP-independent pathways in water deprivation (WD), we investigated AQP2 and phosphorylated AQP2 (p-AQP2) regulation in thirsted adult (10 mo old) and senescent (30 mo old) female WAG/Rij rats. Following 2-day WD, urine flow rate decreased and urine osmolality increased in both groups. However, in agreement with significantly lower cortico-papillary osmotic gradient with aging, urine osmolality remained lower in senescent animals. WD induced sixfold increase of plasma AVP in all animals which, interestingly, did not result in higher papillary cAMP level. Following WD, AQP2 and p-AQP2 expression increased hugely in 10- and 30-mo-old rats and their mistargeting in old animals was corrected. Moreover, the age-related difference in AQP2 regulation was abolished after WD. To further investigate the mechanism of AQP2 underexpression with aging, AQP2 mRNA was quantified by real-time RT-PCR. In the outer medulla, preservation of AQP2 protein expression was achieved through increased AQP2 mRNA level in senescent rats. In the IMCD, no change in AQP2 mRNA was detected with aging but AQP2 protein expression was markedly lower in 30-mo-old animals. In conclusion, there is a posttranscriptional downregulation of AQP2 with aging, which is abolished by WD.
在人类和啮齿动物中，衰老的肾脏与多尿和尿液浓缩能力降低有关。在衰老的雌性WAG/Rij大鼠中，这种缺陷与精氨酸加压素（AVP）/V(2)受体/cAMP途径无关。它被认为是由于髓质内集合管（IMCD）中水通道蛋白2（AQP2）水通道的表达不足和靶向错误。我们之前表明，给予去氨加压素（dDAVP）可以部分纠正这种缺陷。由于在缺水（WD）情况下，AQP2也可由不依赖AVP的途径调节，我们研究了成年（10月龄）和衰老（30月龄）雌性WAG/Rij大鼠在口渴状态下AQP2和磷酸化AQP2（p-AQP2）的调节情况。经过2天的WD后，两组大鼠的尿流率均降低，尿渗透压均升高。然而，与衰老导致皮质-乳头渗透梯度显著降低一致，衰老动物的尿渗透压仍然较低。WD导致所有动物血浆AVP增加了六倍，有趣的是，这并未导致乳头cAMP水平升高。WD后，10月龄和30月龄大鼠的AQP2和p-AQP2表达大幅增加，并且老龄动物中其靶向错误得到纠正。此外，WD后AQP2调节的年龄相关差异消失。为了进一步研究衰老导致AQP2表达不足的机制，通过实时逆转录聚合酶链反应（RT-PCR）对AQP2 mRNA进行定量。在外髓质中，衰老大鼠通过增加AQP2 mRNA水平实现了AQP2蛋白表达的保留。在IMCD中，未检测到衰老导致AQP2 mRNA发生变化，但30月龄动物的AQP2蛋白表达明显较低。总之，衰老导致AQP2发生转录后下调，而WD可消除这种下调。
