Abstract
Background:
Autosomal recessive polycystic kidney disease is a genetic disorder characterized by the development of renal cysts of tubular epithelial cell origin. Epithelial Na+ channel (ENaC) is responsible for sodium reabsorption in the aldosterone-sensitive distal nephron. Here, we investigated the ENaC expression and activity in cystic tissue taken from rats with autosomal recessive polycystic kidney disease.
Methods:
Polycystic kidney (PCK) rats were treated with the selective ENaC inhibitor benzamil given in the drinking water, and after 4 or 12 wk, the severity of morphological malformations in the kidneys was assessed. ENaC and aquaporin-2 expression and ENaC activity were tested with immunohistochemistry and patch-clamp electrophysiology, respectively.
Results:
Treatment with benzamil exacerbated development of cysts compared with the vehicle-treated animals. In contrast, the 12 wk of treatment with the loop diuretic furosemide had no effect on cystogenesis. Single-channel patch-clamp analysis revealed that ENaC activity in the freshly isolated cystic epithelium was significantly lower than that in the noncystic collecting ducts isolated from PCK or normal Sprague-Dawley rats. Immunohistochemical analysis confirmed that β-ENaC and aquaporin-2 expressions in cysts are decreased compared with nondilated tubules from PCK rat kidneys.
Conclusion:
We demonstrated that cystic epithelium exhibits low ENaC activity and this phenomenon can contribute to cyst progression.
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References
Sweeney WE Jr, Avner ED . Pathophysiology of childhood polycystic kidney diseases: new insights into disease-specific therapy. Pediatr Res 2014;75:148–57.
Wilson PD . Polycystic kidney disease. N Engl J Med 2004;350:151–64.
Staruschenko A . Regulation of transport in the connecting tubule and cortical collecting duct. Compr Physiol 2012;2:1541–84.
Rossier BC, Staub O, Hummler E . Genetic dissection of sodium and potassium transport along the aldosterone-sensitive distal nephron: importance in the control of blood pressure and hypertension. FEBS Lett 2013;587:1929–41.
Avner ED, Sweeney WE Jr, Nelson WJ . Abnormal sodium pump distribution during renal tubulogenesis in congenital murine polycystic kidney disease. Proc Natl Acad Sci USA 1992;89:7447–51.
Olteanu D, Yoder BK, Liu W, et al. Heightened epithelial Na+ channel-mediated Na+ absorption in a murine polycystic kidney disease model epithelium lacking apical monocilia. Am J Physiol Cell Physiol 2006;290:C952–63.
Veizis EI, Carlin CR, Cotton CU . Decreased amiloride-sensitive Na+ absorption in collecting duct principal cells isolated from BPK ARPKD mice. Am J Physiol Renal Physiol 2004;286:F244–54.
Rohatgi R, Greenberg A, Burrow CR, Wilson PD, Satlin LM . Na transport in autosomal recessive polycystic kidney disease (ARPKD) cyst lining epithelial cells. J Am Soc Nephrol 2003;14:827–36.
Veizis IE, Cotton CU . Abnormal EGF-dependent regulation of sodium absorption in ARPKD collecting duct cells. Am J Physiol Renal Physiol 2005;288:F474–82.
Katsuyama M, Masuyama T, Komura I, Hibino T, Takahashi H . Characterization of a novel polycystic kidney rat model with accompanying polycystic liver. Exp Anim 2000;49:51–5.
Rohatgi R, Zavilowitz B, Vergara M, Woda C, Kim P, Satlin LM . Cyst fluid composition in human autosomal recessive polycystic kidney disease. Pediatr Nephrol 2005;20:552–3.
Zheleznova NN, Wilson PD, Staruschenko A . Epidermal growth factor-mediated proliferation and sodium transport in normal and PKD epithelial cells. Biochim Biophys Acta 2011;1812:1301–13.
Ryan S, Verghese S, Cianciola NL, Cotton CU, Carlin CR . Autosomal recessive polycystic kidney disease epithelial cell model reveals multiple basolateral epidermal growth factor receptor sorting pathways. Mol Biol Cell 2010;21:2732–45.
Wilson SJ, Amsler K, Hyink DP, et al. Inhibition of HER-2(neu/ErbB2) restores normal function and structure to polycystic kidney disease (PKD) epithelia. Biochim Biophys Acta 2006;1762:647–55.
Wilson PD . Apico-basal polarity in polycystic kidney disease epithelia. Biochim Biophys Acta 2011;1812:1239–48.
MacRae Dell K, Nemo R, Sweeney WE Jr, Avner ED . EGF-related growth factors in the pathogenesis of murine ARPKD. Kidney Int 2004;65:2018–29.
Nemo R, Murcia N, Dell KM . Transforming growth factor alpha (TGF-alpha) and other targets of tumor necrosis factor-alpha converting enzyme (TACE) in murine polycystic kidney disease. Pediatr Res 2005;57(5 Pt 1):732–7.
Frey MR, Brent Polk D . ErbB receptors and their growth factor ligands in pediatric intestinal inflammation. Pediatr Res 2014;75:127–32.
Zhang ZR, Chu WF, Song B, et al. TRPP2 and TRPV4 form an EGF-activated calcium permeable channel at the apical membrane of renal collecting duct cells. PLoS One 2013;8:e73424.
Levchenko V, Zheleznova NN, Pavlov TS, Vandewalle A, Wilson PD, Staruschenko A . EGF and its related growth factors mediate sodium transport in mpkCCDc14 cells via ErbB2 (neu/HER-2) receptor. J Cell Physiol 2010;223:252–9.
Liu L, Duke BJ, Malik B, Yue Q, Eaton DC . Biphasic regulation of ENaC by TGF-{alpha} and EGF in renal epithelial cells. Am J Physiol Renal Physiol 2009;296:F1417–27.
Pavlov TS, Levchenko V, O’Connor PM, et al. Deficiency of renal cortical EGF increases ENaC activity and contributes to salt-sensitive hypertension. J Am Soc Nephrol 2013;24:1053–62.
Pochynyuk O, Bugaj V, Rieg T, et al. Paracrine regulation of the epithelial Na+ channel in the mammalian collecting duct by purinergic P2Y2 receptor tone. J Biol Chem 2008;283:36599–607.
Wilson PD, Hovater JS, Casey CC, Fortenberry JA, Schwiebert EM . ATP release mechanisms in primary cultures of epithelia derived from the cysts of polycystic kidneys. J Am Soc Nephrol 1999;10:218–29.
Schwiebert EM, Wallace DP, Braunstein GM, et al. Autocrine extracellular purinergic signaling in epithelial cells derived from polycystic kidneys. Am J Physiol Renal Physiol 2002;282:F763–75.
Palygin O, Levchenko V, Ilatovskaya DV, et al. Real-time electrochemical detection of ATP and H2O2 release in freshly isolated kidneys. Am J Physiol Renal Physiol 2013;305:F134–41.
Chang MY, Lu JK, Tian YC, et al. Inhibition of the P2X7 receptor reduces cystogenesis in PKD. J Am Soc Nephrol 2011;22:1696–706.
Schwiebert EM . ATP release mechanisms, ATP receptors and purinergic signalling along the nephron. Clin Exp Pharmacol Physiol 2001;28:340–50.
Schwiebert EM, Kishore BK . Extracellular nucleotide signaling along the renal epithelium. Am J Physiol Renal Physiol 2001;280:F945–63.
Torres VE, Harris PC . Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J Am Soc Nephrol 2014;25:18–32.
Rees S, Kittikulsuth W, Roos K, Strait KA, Van Hoek A, Kohan DE . Adenylyl cyclase 6 deficiency ameliorates polycystic kidney disease. J Am Soc Nephrol 2014;25:232–7.
Roos KP, Bugaj V, Mironova E, et al. Adenylyl cyclase VI mediates vasopressin-stimulated ENaC activity. J Am Soc Nephrol 2013;24:218–27.
Kwon M, Pavlov TS, Nozu K, et al. G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease. Proc Natl Acad Sci USA 2012;109:21462–7.
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Pavlov, T., Levchenko, V., Ilatovskaya, D. et al. Impaired epithelial Na+ channel activity contributes to cystogenesis and development of autosomal recessive polycystic kidney disease in PCK rats. Pediatr Res 77, 64–69 (2015). https://doi.org/10.1038/pr.2014.145
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DOI: https://doi.org/10.1038/pr.2014.145
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