The Tibetan antelope (Pantholops hodgsonii) is endemic to the extremely inhospitable high-altitude environment of the Qinghai-Tibetan Plateau, a region that has a low partial pressure of oxygen and high ultraviolet radiation. Here we generate a draft genome of this artiodactyl and use it to detect the potential genetic bases of highland adaptation. Compared with other plain-dwelling mammals, the genome of the Tibetan antelope shows signals of adaptive evolution and gene-family expansion in genes associated with energy metabolism and oxygen transmission. Both the highland American pika, and the Tibetan antelope have signals of positive selection for genes involved in DNA repair and the production of ATPase. Genes associated with hypoxia seem to have experienced convergent evolution. Thus, our study suggests that common genetic mechanisms might have been utilized to enable high-altitude adaptation.

Efficient gas exchange in the lungs depends on regulation of the amount of fluid in the thin (average 0.2 m) liquid layer lining the alveolar epithelium. Fluid fluxes are regulated by ion transport across the alveolar epithelium, which is composed of alveolar type I (TI) and type II (TII) cells. The accepted paradigm has been that TII cells, which cover <5% of the internal surface area of the lung, transport Na ؉ and Cl ؊ and that TI cells, which cover >95% of the surface area, provide a route for water absorption. Here we present data that TI cells contain functional epithelial Na ؉ channels (ENaC), pimozide-sensitive cation channels, K ؉ channels, and the cystic fibrosis transmembrane regulator. TII cells contain ENaC and cystic fibrosis transmembrane regulator, but few pimozide-sensitive cation channels. These findings lead to a revised paradigm of ion and water transport in the lung in which (i) Na ؉ and Cl ؊ transport occurs across the entire alveolar epithelium (TI and TII cells) rather than only across TII cells; and (ii) by virtue of their very large surface area, TI cells are responsible for the bulk of transepithelial Na ؉ transport in the lung.S hortly before birth, the fetal lung converts from fluid secretion to fluid reabsorption. After birth, efficient gas exchange depends on regulation of the amount of fluid in the thin (average, 0.2 m) liquid layer lining the alveolar epithelium (1). Alveolar flooding resulting from cardiogenic pulmonary edema or acute lung injury impairs gas diffusion across the air͞blood barrier; an increase in alveolar fluid clearance restores a normal air͞blood barrier. Alveolar fluid transport from alveolar to interstitial spaces, driven by active Na ϩ transport across the alveolar epithelium (2), can be inhibited either by the addition of amiloride, a Na ϩ channel inhibitor, to the alveolar space, or ouabain, a Na ϩ ,K ϩ -ATPase inhibitor, to the vascular bed (3), suggesting that the alveolar epithelium is the major site of Na ϩ transport and fluid absorption in the adult lung.The alveolar epithelium, which covers Ͼ99% of the large internal surface area of the lung (4), is composed of two cell types, alveolar type I (TI) and type II (TII) cells. TII cells, which cover 2-5% of the internal surface area of the lung, are cuboidal cells that synthesize and secrete pulmonary surfactant. TII cells contain ion channels, including the amiloride-sensitive epithelial Na ϩ channel (ENaC) (5), Na ϩ ,K ϩ -ATPase (3) and the cystic fibrosis transmembrane regulator (CFTR) (6). TI cells are large squamous cells whose thin cytoplasmic extensions cover Ͼ95% of the internal surface area of the lung (7). TI cells express aquaporin 5, a water channel (8), and have the highest known osmotic water permeability of any mammalian cell type (9). The observations that TII cells contain ion channels and TI cells express aquaporins led to the paradigm that TII cells govern alveolar fluid balance by regulating Na ϩ transport in the lungs, whereas TI cells merely provide a route for passive water absorpti...

The epithelial Na ϩ channel, ENaC, and the Cl Ϫ /HCO 3 Ϫ exchanger, pendrin, mediate NaCl absorption within the cortical collecting duct and the connecting tubule. Although pendrin and ENaC localize to different cell types, ENaC subunit abundance and activity are lower in aldosterone-treated pendrin-null mice relative to wild-type mice. Because pendrin mediates HCO 3 Ϫ secretion, we asked if increasing distal delivery of HCO 3 Ϫ through a pendrin-independent mechanism "rescues" ENaC function in pen- 21: 192821: -194121: , 201021: . doi: 10.1681 Pendrin, encoded by Slc26a4, is an aldosterone-sensitive Cl Ϫ /HCO 3 Ϫ exchanger that mediates Cl Ϫ absorption and HCO 3 Ϫ secretion in the cortical collecting duct (CCD). 1-3 During NaCl restriction, pendrin-null mice excrete more NaCl than wild-type mice, which increases apparent vascular volume contraction and lowers BP. [3][4][5] The chloruresis observed in pendrin-null mice during NaCl restriction likely results from the absence of pendrin-mediated Cl Ϫ absorption. 3,4 However, because pendrin does not transport Na ϩ , the cause of the natriuresis observed in the mutant mice was explored further. After either dietary NaCl restriction or the administration of aldosterone, renal ENaC function and ENaC subunit abundance were lower in pendrin-null mice than in wildtype mice. 5 In particular, ␥ ENaC abundance was reduced in kidneys from pendrin-null mice relative to wild-type mice. However, how pendrin J Am Soc Nephrol

Amiloride-sensitive epithelial Na؉ channels (ENaC) are responsible for trans-epithelial Na

Regulation of epithelial Na؉ channel (ENaC) subunit levels by protein kinase C (PKC) was investigated in A6 cells. PKC activation altered ENaC subunit levels, differentially decreasing the levels of both ␤ and ␥, but not ␣ENaC. Temporal regulation of ␤ and ␥ENaC by PKC differed; ␥ENaC decreased with a time constant of 3.7 ؎ 1.0 h, whereas ␤ENaC decreased in 13.9 ؎ 3.0 h. Activation of PKC also resulted in a decrease in trans-epithelial Na ؉ reabsorption for up to 48 h. PMA activation of PKC resulted in negative feedback inhibition of PKC protein levels beginning within 4 h. Both ␤ and ␥ENaC levels, as well as transport tended toward pretreatment values after 48 h of PMA treatment. PKC inhibitors attenuated the effects of PMA on ENaC subunit levels and Na ؉ transport. These results directly show for the first time that PKC differentially regulates ENaC subunit levels by decreasing the levels of ␤ and ␥ but not ␣ENaC protein. These results imply a PKC-dependent, long term decrease in Na ؉ reabsorption.Sodium homeostasis is essential to proper maintenance of total body water and electrolyte content, and thus, blood pressure control. The activity of luminal, epithelial Na ϩ channels (ENaC) 1 is rate-limiting for trans-epithelial Na ϩ reabsorption across the renal collecting duct and other Na ϩ reabsorbing epithelium. Thus, understanding regulation of ENaC activity is relevant to physiology as well as to treating disease with associated fluid imbalance.ENaC is a heterotetrameric channel complex composed of at least three homologous but distinct subunits: ␣, ␤, and ␥ (1). Numerous results show that expression of ENaC subunit message and protein are differentially regulated in various tissues and species (reviewed by Refs. 2-4). For example, Masilamani and colleagues (5) recently showed in rat collecting duct principal cells that ␣ENaC protein levels increase in response to aldosterone; however, we found in the amphibian A6 cell model of the collecting duct principal cell that ␣ENaC is not significantly influenced by aldosterone, but ␤ENaC protein levels are increased in response to steroid (Ref. 6; also refer to Fig. 1 of the present study). Besides aldosterone, Zentner et al. (7) recently showed in the rat parotid epithelial cell line, Pa-4, that expression of ␣ENaC mRNA and possibly protein was decreased within 6 h by protein kinase C activation.Activation of PKC decreases Na ϩ reabsorption across renal epithelium by affecting ENaC (8 -11). Studies of single channel properties show that in amphibian, rat, and rabbit distal tubule cells, ENaC activity is decreased within 5-10 min after activation of PKC (12-15). A rapid initial decrease in ENaC open probability is, in part, responsible for the early change in activity; however, it appears that PKC may also subsequently affect the number of functional channels (14, 15). Although most studies are consistent with PKC decreasing ENaC open probability initially and then subsequently reducing channel number, Els et al. (16) showed with blocker-induced noise analysis in A6...