Abstract
Acute rejection in renal transplantation disturbs solute and volume maintenance in humans accompanied by delayed graft function and poor prognosis. We recently reported that decreased expression and function of Na+/H+ exchanger type 3 (NHE-3) in proximal tubules and epithelial Na+ channels and aquaporin 2 in collecting ducts are major mechanisms involved in Na+ and water imbalances shortly after transplantation in rat undergoing acute rejection. We performed kidney transplantations in rats with bilaterally nephrectomized recipients with acute rejection and, in addition, systemically administered a specific inhibitor of NHE-3 (NHE-I). NHE inhibition in acute renal failure was shown to improve tubular function and recovery. The aim of this therapy was to reduce energy consumption of the graft and preserve NHE-3 function. Imbalances in electrolyte excretion declined in NHE-I-treated animals and NHE-3 activity was preserved. Observed NHE-I-dependent changes in electrolyte excretion, polyuria, and reduced protein reabsorption in the acute postoperative phase are predictors of favorable graft outcome in humans.
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References
Batlle DC, Mozes MF, Manaligod J et al (1981) The pathogenesis of hyperchloremic metabolic acidosis associated with kidney transplantation. Am J Med 70:786–796
Curtis JJ (1994) Hypertension following kidney transplantation. Am J Kidney Dis 23:471–475
Heering P, Degenhardt S, Grabensee B (1996) Tubular dysfunction following kidney transplantation. Nephron 74:501–511
Ogden AD, Sitprija V, Holmes JH (1965) Function of the renal homograft in man immediately after transplantation. Am J Med 38:873–882
Beckerhoff R, Uhlschmid G, Vetter W et al (1974) Plasma renin and aldosterone after renal transplantation. Kidney Int 5:39–46
Henderson LW, Nolph KD, Puschett JB et al (1968) Proximal tubular malfunction for diuresis after renal homotransplantation. New Engl J Med 278:467–473
Velic A, Gabriëls G, Hirsch JR et al (2005) Acute rejection after rat renal transplantation leads to downregulation of Na+ and water channels in the collecting duct. Am J Transplant 5:1276–1285
Velic A, Hirsch JR, Bartels J et al (2004) Renal transplantation modulates expression and function of receptors and transporters of rat proximal tubules. J Am Soc Nephrol 15:967–977
Matteucci E, Carmellini M, Mosca F et al (1999) The contribution of Na+/H+ exchange to postreperfusion injury and recovery of transplanted kidney. Biomed Pharmacother 53:438–444
de Seigneux S, Nielsen J, Olesen ET et al (2007) Long-term aldosterone treatment induces decreased apical but increased basolateral expression of AQP2 in CCD of rat kidney. Am J Physiol Renal Physiol 293:F87–F99
Alexander RT, Malevanets A, Durkan AM et al (2007) Membrane curvature alters the activation kinetics of the epithelial Na+/H+ exchanger, NHE3. J Biol Chem 282:7376–7384
Hropot M, Juretschke HP, Langer KH (2001) S3226, a novel NHE3 inhibitor, attenuates ischemia-induced acute renal failure in rats. Kidney Int 60:2283–2289
Gekle M, Drumm K, Mildenberger S (1999) Inhibition of Na+–H+ exchange impairs receptor-mediated albumin endocytosis in renal proximal tubule-derived epithelial cells from opossum. J Physiol 520:709–721
Gekle M, Volker K, Mildenberger S (2004) NHE3 Na+/H+ exchanger supports proximal tubular protein reabsorption in vivo. Am J Physiol Renal Physiol 287:F469–F473
Wohlfarth V, Drumm K, Mildenberger S et al (2003) Protein uptake disturbs collagen homeostasis in proximal tubule derived cells. Kidney Int 84:S103–S109
Drumm K, Gassner B, Silbernagl S et al (2001) Inhibition of Na+/H+ exchange decreases albumin-induced NF-kB activation in renal proximal tubular cell lines (OK and LLC-PK1 cells). Eur J Med Res 6:422–432
Eddy AA (1996) Expression of genes that promote renal interstitial fibrosis in rats with proteinuria. Kidney Int 54:S49–S54
Drumm K, Lee E, Stanners S et al (2003) Albumin and glucose effects on cell growth parameters, albumin uptake and Na+/H+-exchanger isoform 3 in OK cells. Cell Physiol Biochem 13:199–206
Christensen EI, Birn H (2001) Megalin and cubilin: synergistic endocytic receptors in renal proximal tubule. Am J Physiol Renal Physiol 280:F562–F573
Verroust PJ, Birn H, Nielsen R et al (2002) The tandem endocytic receptors megalin and cubilin are important proteins in renal pathology. Kidney Int 62:745–56
Matteucci E, Carmellini M, Bertoni C et al (1998) Urinary excretion rates of multiple renal indicators after kidney transplantation: clinical significance for early graft outcome. Ren Fail 20:325–330
Bleich M, Sievers B, Himmerkus N et al (2005) Acute inhibition of NHE3 and kidney function. Pflügers Arch 1(449 Suppl):19–40
Sievers B, Shan Q, Himmerkus N et al (2005) Renal compensation of pharmacological NHE3 knockout. Pflügers Arch 1(449 Suppl):91–110
Gabriëls G, August C, Grisk O et al (2003) Impact of renal transplantation on small vessel reactivity. Transplantation 75:689–697
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408
Schlatter E, Haxelmans S, Ankorina I (1995) Regulation of Na+/H+ exchange by diadenosine polyphosphates, angiotensin II, and vasopressin in rat cortical collecting duct. J Am Soc Nephrol 6:1223–1229
Schäfer JA, Watkins ML, Li L et al (1997) A simplified method for isolation of large numbers of defined nephron segments. Am J Physiol 273:F650–F657
Schlatter E, Fröbe U, Greger R (1992) Ion conductances of isolated cortical collecting duct cells. Pflügers Arch 421:381–387
Schlatter E, Haxelmans S, Ankorina I (1996) Correlation between intracellular activities of Ca2+and Na+ in rat cortical collecting duct—a possible coupling mechanism between Na+-K+-ATPase and basolateral K+ conductance. Kidney Blood Press Res 19:24–31
Manfredi G, Yang L, Gajewski CD et al (2002) Measurements of ATP in mammalian cells. Methods 26:317–26
Acknowledgment
The excellent technical help from Mrs. Ute Neugebauer is gratefully acknowledged. This study was supported by a grant from the Else-Kröner-Fresenius Foundation (P22/05//A43/05//F00) to E.S.
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Stefan Reuter and Ana Velic contributed equally to this study.
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Reuter, S., Velic, A., Edemir, B. et al. Protective role of NHE-3 inhibition in rat renal transplantation undergoing acute rejection. Pflugers Arch - Eur J Physiol 456, 1075–1084 (2008). https://doi.org/10.1007/s00424-008-0484-7
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DOI: https://doi.org/10.1007/s00424-008-0484-7