Changes in aquaporin-2 protein contribute to the urine concentrating defect in rats fed a low-protein diet.

Sands, Jeff M.; Naruse, Masahiro; Jacobs, Joely D.; Wilcox, Josiah N.; Klein, Janet D.

doi:10.1172/jci118736

Cited by 87 publications

(42 citation statements)

References 45 publications

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“…Urea, along with sodium chloride, constitutes a large portion of the medullary hyperosmolar driving force for water transport; therefore, diminished protein intake as reflected by decreased urinary urea excretion could contribute to the concentrating defect in hypothyroidism. In this regard, protein restriction has been shown to decrease maximal urinary concentration (16). In preliminary studies, we observed a decreased intake of protein and calories in the hypothyroid rats.…”

Section: Discussionmentioning

confidence: 57%

Urinary Concentrating Defect in Hypothyroid Rats

Cadnapaphornchai¹,

Kim²,

Gurevich³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Hypothyroidism is associated with impaired urinary concentrating ability in humans and animals. The purpose of this study was to examine protein expression of renal sodium chloride and urea transporters and aquaporins in hypothyroid rats (HT) with diminished urinary concentration as compared with euthyroid controls (CTL) and hypothyroid rats replaced with L-thyroxine (HTϩT). Hypothyroidism was induced by aminotriazole administration. Body weight, water intake, urine output, solute and urea excretion, serum and urine osmolality, serum creatinine, 24-h creatinine clearance, and fractional excretion of sodium were comparable among the three groups. However, with 36 h of water deprivation, HT rats demonstrated significantly greater urine flow rates and decreased urine and medullary osmolality as compared with CTL and HTϩT rats at comparable plasma vasopressin concentrations. Western blot analyses revealed decreased renal protein abundance of transporters, including Na-K-2Cl, Na-K-ATPase, and NHE3, in HT rats as compared with CTL and HTϩT rats. Protein abundance of renal AQP1 and urea transporters UTA 1 and UTA 2 did not differ significantly among study groups. There was however a significant decrease in protein abundance of AQP2, AQP3, and AQP4 in HT rats as compared with CTL and HTϩT rats. These findings demonstrate a decrease in the medullary osmotic gradient secondary to impaired countercurrent multiplication and downregulation of aquaporins 2, 3, and 4 as contributors to the urinary concentrating defect in the hypothyroid rat.Hypothyroidism is a very common clinical disorder that is associated with abnormalities in many organs, including the kidney. The ability to conserve water during periods of fluid deprivation is an important function of the kidney. Hypothyroidism has been associated with an impaired urinary concentrating capacity (1,2). However, the mechanisms of this defect at the cellular and molecular level have not been defined.In the present study, the effect of hypothyroidism in rats on the pivotal components of the urinary concentrating mechanism have been examined and compared with euthyroid animals. These components during fluid deprivation include release of the antidiuretic hormone, arginine vasopressin (AVP), and upregulation of the abundance of aquaporin-2 (AQP2) water channels in the principal cells of the collecting duct. Activation of the countercurrent concentrating mechanism, which is initiated by increased sodium-potassium-2 chloride (Na-K-2Cl) co-transporter in the water impermeable ascending limb, creates the osmotic driving force for passive water reabsorption across the collecting duct. There are also roles for other water channels, including aquaporins 1, 3, and 4, and for urea transporters in urinary concentration. The present study was undertaken to define the effect of hypothyroidism on these various molecular events during fluid deprivation in the rat. Materials and Methods Animal ModelThe study protocol was approved by the University of Colorado Institutional Animal Ca...

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Section: Discussionmentioning

confidence: 57%

Urinary Concentrating Defect in Hypothyroid Rats

Cadnapaphornchai¹,

Kim²,

Gurevich³

et al. 2003

Journal of the American Society of Nephrology

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“…To preserve urea delivery to the deep IM, the model assumed that CD urea permeability was low throughout the OM and the initial 1/5 of the IM (3 ϫ 10 Ϫ6 cm/s), which is not inconsistent with low urea permeability values reported in microperfusion studies (36) or those used in mathematical models of the CD (43,44), although our values may correspond to the lower limit. To study the impact of a slightly higher, but still low, OM and early IMCD urea permeability, we conducted a simulation in which CD urea permeability was set to 1 ϫ 10 Ϫ5 cm/s in the OM and in the initial one-fifth of the IM.…”

Section: Urea Permeabilitymentioning

confidence: 86%

A mathematical model of the urine concentrating mechanism in the rat renal medulla. II. Functional implications of three-dimensional architecture

Layton

2011

American Journal of Physiology-Renal Physiology

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.2010] a region-based mathematical model was formulated for the urine concentrating mechanism in the renal medulla of the rat kidney. In the present study, we investigated model sensitivity to some of the fundamental structural assumptions. An unexpected finding is that the concentrating capability of this region-based model falls short of the capability of models that have radially homogeneous interstitial fluid at each level of only the inner medulla (IM) or of both the outer medulla and IM, but are otherwise analogous to the region-based model. Nonetheless, model results reveal the functional significance of several aspects of tubular segmentation and heterogeneity: 1) the exclusion of ascending thin limbs that reach into the deep IM from the collecting duct clusters in the upper IM promotes urea cycling within the IM; 2) the high urea permeability of the lower IM thin limb segments allows their tubular fluid urea content to equilibrate with the surrounding interstitium; 3) the aquaporin-1-null terminal descending limb segments prevent water entry and maintain the transepithelial NaCl concentration gradient; 4) a higher thick ascending limb Na ϩ active transport rate in the inner stripe augments concentrating capability without a corresponding increase in energy expenditure for transport; 5) active Na ϩ reabsorption from the collecting duct elevates its tubular fluid urea concentration. Model calculations predict that these aspects of tubular segmentation and heterogeneity promote effective urine concentrating functions.kidney; loops of Henle; aquaporin-1; collecting duct; Na ϩ transport; urea transport IN A COMPANION PAPER (19), which we refer to as study 1, we formulated a region-based mathematical model of the urine concentrating mechanism in the renal medulla of the rat kidney. The general aim of study 1, and of this study, which we call study 2, is to investigate the effects of structural heterogeneity in the urine concentrating mechanism of the renal medulla.As noted in our recent reviews (22, 34), we believe that the urine concentrating mechanism should be considered in light of the radial and axial inhomogeneity revealed in anatomic studies. Kriz and colleagues (13,14,16,18) have reported that the organization of tubules and vessels is highly structured in the outer medulla (OM) of a number of mammalian species, including rats and mice. Tubules are organized around tightly packed vascular bundles, with the collecting ducts (CDs) and thick ascending limbs (TALs) found distant from vascular bundles and descending limbs positioned nearer the bundles. Cluster of CDs form the dominant organizing structural elements for the arrangement of the tubules and vessels in the inner medulla (IM) (30, 32). In the upper IM, the descending thin limbs of Henle's loops and descending vasa recta (DVR) are nearly always located outside and surrounding the CD clusters (31, 32). In contrast, the ascending thin limbs and ascending vasa recta (AVR) are arranged nearly uniformly across the IM, both inside and outside the CD cl...

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“…There is also multiple, but mechanistically unexplained, evidence for an AVP-independent regulation of the water permeability of principal cells in the intact animal (30). Decreased AQP2 expression without changes in AVP or cAMP levels was observed in fasting and protein-deprived rats and humans (1,35). Water deprivation increased AQP2 expression in rats chronically given V 2 R antagonists (24), indicating that the effect of water deprivation on AQP2 expression is not solely due to AVP-elicited cAMP accumulation.…”

Section: Discussionmentioning

confidence: 99%

Osmolality and solute composition are strong regulators of AQP2 expression in renal principal cells

Storm

Klussmann

Geelhaar

et al. 2003

American Journal of Physiology-Renal Physiology

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. Osmolality and solute composition are strong regulators of AQP2 expression in renal principal cells. Am J Physiol Renal Physiol 284: F189-F198, 2003. First published August 13, 2002; 10.1152/ajprenal.00245.2002The water permeability of the renal collecting duct is regulated by the insertion of aquaporin-2 (AQP2) into the apical plasma membrane of epithelial (principal) cells. Using primary cultured epithelial cells from the inner medulla of rat kidney (IMCD cells), we show that osmolality and solute composition are potent regulators of AQP2 mRNA and protein synthesis, as well as the classical cAMP-dependent pathway, but do not affect the arginine vasopressin-induced AQP2 shuttle. In the presence of the cAMP analog dibutyryl cAMP (DBcAMP, 500 M), NaCl and sorbitol, but not urea, evoked a robust increase of AQP2 expression in IMCD cells, with NaCl being far more potent than sorbitol. cAMP-responsive elementbinding protein phosphorylation increased with DBcAMP concentrations but was not altered by changes in osmolality. In the rat and human AQP2 promoter, we identified a putative tonicity-responsive element. We conclude that, in addition to the arginine vasopressin/cAMP-signaling cascade, a further pathway activated by elevated effective osmolality (tonicity) is crucial for the expression of AQP2 in IMCD cells, and we suggest that the effect is mediated via the tonicityresponsive element. osmolality; aquaporin-2; kidney; gene regulation; toxicity responsive enhancer THE WATER CHANNEL aquaporin-2 (AQP2), expressed in epithelial (principal) cells of renal collecting ducts, is required for the vasopressin-dependent concentration of urine (7). AQP2 abundance increases from the kidney cortex to the inner region of the kidney medulla (29), as does osmolality. The water permeability of the inner medullary collecting duct (IMCD) is rapidly regulated (within minutes) by the antidiuretic hormone arginine vasopressin (AVP), which binds to heptahelical vasopressin V 2 receptors (V 2 R), located mainly in the basolateral plasma membrane of principal cells. Activation of the V 2 R causes stimulation of adenylyl cyclase via the G protein G S , leading to elevation of cAMP. The subsequent activation of protein kinase A (PKA) initiates the translocation of AQP2-bearing vesicles from the cytosol to the plasma membrane, in which AQP2 is inserted by an exocytosis-like process (short-term regulation) (D. Lorenz, A. Krylov, V. Hagen, J. Zipper, W. Rosenthal, P. Pohl, and K. Maric, unpublished observations; 30). In addition, the signaling cascade described above governs the expression of AQP2 (long-term regulation) by PKA-mediated phosphorylation of the transcription factor cAMP-responsive element (CRE)-binding protein (CREB) (13,16). Given the fact that AQP2 biosynthesis is usually shut off shortly after IMCD cells are established in primary culture (10), most studies on AQP2 long-term regulation have been performed using animal models (29, 37). We recently established primary cultured IMCD cells as a model system (17,18,21,22). Thes...

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Changes in aquaporin-2 protein contribute to the urine concentrating defect in rats fed a low-protein diet.

Cited by 87 publications

References 45 publications

Urinary Concentrating Defect in Hypothyroid Rats

Urinary Concentrating Defect in Hypothyroid Rats

A mathematical model of the urine concentrating mechanism in the rat renal medulla. II. Functional implications of three-dimensional architecture

Osmolality and solute composition are strong regulators of AQP2 expression in renal principal cells

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