Endothelin in Renal Physiology and Disease

Editor(s): Barton M. (Zürich) 
Kohan D.E. (Salt Lake City, Utah) 
Table of Contents
Vol. 172, 2011
Section title: Molecular Biology and Physiology of Endothelin in the Kidney
Barton M, Kohan DE (eds): Endothelin in Renal Physiology and Disease. Contrib Nephrol. Basel, Karger, 2011, vol 172, pp 107–119

Endothelin in the Control of Renal Sympathetic Nerve Activity

Kopp U.C.
Departments of Internal Medicine and Pharmacology, University of Iowa Carver, College of Medicine and Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA

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The kidney is densely innervated by sympathetic nerves. Increases in renal sympathetic nerve activity (RSNA) decrease urinary sodium excretion. The kidney also has abundant afferent sensory innervation, located primarily in the renal pelvic wall. Sympathetic nerve fibers and afferent nerve fibers often run separately but intertwined in the same nerve bundles in the renal pelvic wall, providing anatomic support for a functional interaction between RSNA and afferent renal nerve activity (ARNA). Activation of RSNA increases ARNA, which in turn decreases RSNA by activation of the renorenal reflexes. Thus, RSNA-induced increases in ARNA exert a powerful negative feedback control of RSNA via activation of the renorenal reflexes in the overall goal of maintaining low RSNA to facilitate urinary sodium excretion. A high-sodium diet enhances and a low-sodium diet reduces the RSNA-induced increases in ARNA. The physiologic importance of the dietary-induced changes in the RSNA-mediated increases in ARNA is underlined by salt-sensitive hypertension in rats lacking afferent renal innervation. Endothelin (ET), ETA receptors (R), and ETB-R are present in the renal pelvic wall. ET plays a modulatory role in the activation of the afferent renal nerves that is dependent on dietary sodium intake. In a high-sodium diet, increased activation of ETB-R facilitates the interaction between RSNA and ARNA resulting in suppression of RSNA, via activation of the renorenal reflexes, to limit sodium retention. In a low-sodium diet, increased activation of renal pelvic ETA-R suppresses the interaction between RSNA and ARNA which increases RSNA via impairment of the renorenal reflex mechanism, eventually leading to sodium retention. These findings suggest that the increased renal sympathetic nerve activity and salt-sensitive hypertension in ET-1/ETB-R-deficient subjects is, at least in part, related to suppressed interaction between RSNA and ARNA.

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  1. Dibona GF, Kopp UC: Neural control of renal function. Physiol Rev 1997;77:75-197
  2. Kopp UC, Cicha MZ., Smith LA, Mulder J, Hokfelt T: Renal sympathetic nerve activity modulates afferent renal nerve activity by PGE2-dependent activation of α1- and α2-adrenoceptors on renal sensory nerve fibers. Am J Physiol 2007;293:R1561-R1572
  3. Takagi H, Hisa H, Satoh S: Effects of endothelin on adrenergic neurotransmission in the dog kidney. Eur J Pharmacol 1991;203:291-294
  4. Matsuo G, Matsumura Y, Tadano K, Hashimoto T, Morimoto S: Involvement of nitric oxide in endothelin ETB receptormediated inhibitory actions on antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs. J Cardiovasc Pharmacol 1997;30:325-331
  5. Matsumura Y, Matsuo G, Egi Y, Tadano K, Morimoto S: Inhibitory effects of endothelin-3 on antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs. J Cardiovasc Pharmacol 1996;28:278-284
  6. Boesen EI, Anderson WP, Evans RG, Kett MM: Endogenous endothelins and the response to electrical renal nerve stimulation in anaesthetized rabbits. Autonom Neurosci 2007;132:8-15
  7. Reid JJ: Endothelin-1 may be a physiological modulator of vasoconstriction in rat kidney. J Cardiovasc Pharmacol 1993;22:((suppl 8))s67-s70
  8. Ling G-Y, Cao W-H, Onodera M, Ju K-H, Kurihara H, Kurihara Y, Yazaki Y, Kumada M, Fukuda Y, Kuwaki T: Renal sympathetic nerve activity in mice: comparison between mice and rats and between normal and endothelin-1 deficient mice. Brain Res 1998;808:238-249
  9. Ohkita M, Wang Y, Nguyen NDT, Tsai Y-H: Williams SC, Wiseman RC, Killen PD, Li S: Yanagisawa M, Gariepy CE: Extrarenal ETB plays a significant role in controlling cardio-vascular responses to high dietary sodium in rats. Hypertension 2005;45:940-946
  10. Kopp UC, Grisk O, Cicha MZ, Smith LA, Steinbach A, Schlüter T, Mähler N, Hökfelt: Dietary sodium modulates the interaction between efferent renal sympathetic nerve activity and afferent renal nerve activity: role of endothelin. Am J Physiol 2009;297:R337-R351
  11. Pollock DM, Pollock JS: Evidence for endothelin involvement in the response to high salt. Am J Physiol 2001;281:F144-F150
  12. Giaid A, Gibson SJ, Ibrahim NBN, Legon S, Bloom SR, Yanagisawa M, Masaki T, Varndell IM, Polak JM: Endothelin 1, an endothelium-derived peptide, is expressed in neurons of the human spinal cord and dorsal root ganglia. Proc Natl Acad Sci USA 1989;86:7634-7638
  13. Klass M, Hord A, Wilcox M, Denson D, Csete M: A role for endothelin in neuropathic pain after constriction injury of the sciatic nerve. Anesth Analg 2005;101:1757-1762
  14. Ahn D, Ge Y, Stricklett PK, Gill P, Taylor D, Hughes AK, Yanagisawa M, Miller L, Nelson RD, Kohan DE: Collecting duct-specific knockout of endothelin-1 causes hypertension and sodium retention. J Clin Invest 2004;114:504-511
  15. Ye DZ, Wang DH: Function and regulation of endothelin-1 and its receptors in salt sensitive hypertension induced by sensory nerve degeneration. Hypertension 2002;39:673-678
  16. Rubanyi GM, Polokoff MA: Endothelins: molecular biology, biochemistry, pharmacology, physiology and pathophysiology. Pharmacol Rev 1994;46:325-415
  17. Itoh S, van den Buuse M: Sensitization of baroreceptor reflex by central endothelin in conscious rats. Am J Physiol 1991;260:H1106-H1112
  18. Li DP, Fan MZ, He RR: Effects of endothelin on carotid baroreceptor activity in anesthetized rats. Sheng Li Xu Bao 1998;50:532-538
  19. Kopp UC, Jones SY, DiBona GF: Afferent renal denervation impairs baroreflex control of efferent renal sympathetic nerve activity. Am J Physiol 2008;295:R1882-R1890
  20. Kopp UC, Cicha MZ, Smith LA, Ruohonen S, Scheinin M, Fritz N, Hökfelt T: Dietary sodium modulates the interaction between efferent and afferent renal nerve activity by altering activation of α2-adrenoceptors on renal sensory nerves. Am J Physiol 2011;300:R298-R310
  21. Liu L, Barajas L: The rat renal nerves during development. Anat Embryol 1993;188:345-361
  22. Kopp UC, Smith LA, Pence A: Na+- K+-ATPase inhibition sensitizes renal mechano-receptors activated by physiological increases in renal pelvic pressure. Am J Physiol 1994;267:R1109-R1117
  23. Genovesi S, Pieruzzi F, Wijnmaalen P, Centonza L, Golin R, Zanchetti A, Stella A: Renal afferents signaling diuretic activity in the cat. Circ Res 1993;73:906-913
  24. Kopp UC, Smith LA, DiBona GF: Impaired renorenal reflexes in spontaneously hypertensive rats. Hypertension 1987;9:69-75
  25. Kopp UC, Cicha MZ, Smith LA: Impaired interaction between efferent and afferent renal nerve activity in SHR involves increased activation of a2- adrenoceptors. Hypertension 2011;57:640-647
  26. Kopp UC, Farley DM, Cicha MZ, Smith LA: Activation of renal mechanosensitive neurons involves bradykinin, protein kinase C, PGE2 and substance P. Am J Physiol 2000;278:R937-R946
  27. Kopp UC, Cicha MZ, Nakamura K, Nüsing RM, Smith LA, Hökfelt T: Activation of EP4 receptors contributes to prostaglandin E2 mediated stimulation of renal sensory nerves. Am J Physiol 2004;287:F1269-F1282
  28. Manning DC, Snyder SH: Bradykinin receptors localized by quantitative autoradiography in kidney, ureter, and bladder. Am J Physiol 1989;256:F909-F915
  29. Kopp UC, Cicha MZ, Smith LA Haeggström JZ, Samuelsson B, Hökfelt T: Cyclooxygenase-2 involved in stimulation of renal mechanosensitive neurons. Hypertension 2000;35:373-378
  30. Kopp UC, Cicha MZ: PGE2 increases substance P release from renal pelvic sensory nerves via activation of N-type calcium channels. Am J Physiol 1999;276:R1241-R1248
  31. Hou L, Wang X: PKC and PKA, but not PKG mediate LPS induced CGRP release and [Ca2]i elevation in DRG neurons of neonatal rats. J Neurosci Res 2001;66:592-600
  32. Kopp UC, Cicha MZ, Smith LA: Angiotensin blocks substance P release from renal sensory nerves by inhibiting PGE2- mediated activation of cAMP. Am J Physiol Renal Physiol 2003;285:F472-F483
  33. Kopp UC, Cicha MZ, Smith LA: Endogenous angiotensin modulates PGE2- mediated release of substance P from renal mechanosensory nerve fibers. Am J Physiol 2002;282:R19-R30
  34. Kopp UC, Cicha MZ, Smith LA: PGE2 increases release of substance P from renal sensory nerves by activating the cAMP-PKA transduction cascade. Am J Physiol 2002;282:R1618-R1627
  35. Kopp UC, Cicha MZ, Smith LA: Differential effects of endothelin on the activation of renal mechanosensory nerves: stimulatory in high and inhibitory in low sodium diet. Am J Physiol Regul Integr Comp Physiol 2006;291:R1545-R1556
  36. Donovan MK, Wyss JM, Winternitz SR: Localization of renal sensory neurons using fluorescent dye technique. Brain Res 1983;259:119-122
  37. Kopp UC, Cicha MZ, Smith LA: Activation of endothelin-A receptors contributes to angiotensin-induced suppression of renal sensory nerve activation. Hypertension 2007;49:141-147
  38. Ito H, Hirata Y, Adachi S, Tanaka M, Tsujino M, Koike A, Nogami A, Marumo F, Hiroe M: Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest 1993;93:398-403
  39. Rajagopalan S, Laursen JB, Borthayre A, Kurz S, Keiser J, Haleen S, Giaid A, Harrison DG: Role for endothelin-1 in angiotensin II-mediated hypertension. Hypertension 1997;30:29-34
  40. Koyama Y, Mizobata T, Yamamoto N, Hashimoto H, Matsuda T, Baba A: Endothelins stimulate expression of cyclooxygenase 2 in rat cultured astrocytes. J Neurochem 1999;73:1004-1011
  41. Verkhratsky A, Orkand RA, Kettenmann H: Glial calcium: homeostasis and signalling function. Physiol Rev 1998;78:99-141
  42. Loomis ED, Sullivan JC, Osmond DA, Pollock DM, Pollock JS: Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta. J Pharmacol Exp Ther 2005;315:1058-1064
  43. Li Z, Mao HZ, Abboud FM, Chapleau MW: Oxygen-derived free radical contribute to baroreceptor dysfunction in atherosclerotic rabbits. Cir Res 1996;79:802-811
  44. Kopp UC, Cicha MZ, Jones SY: Activation of endothelin A receptors contributes to impaired responsiveness of renal mechanosensory nerves in congestive heart failure. Can J Physiol Pharmacol 2010;88:622-629
  45. Motte S, van Beneden R, Mottet J, Rondolet B, Mathieu M, Havaux X, Lause P, Clercx C, Ketelslegers JM, Naeije R, McEntee K: Early activation of cardiac and renal endothelin systems in experimental heart failure. Am J Physiol 2003;285:H2482-H2491
  46. Luchner A, Jougasaki M, Friedrich E, Borgeson DD, Stevens TL, Redfield MM, Riegger GAJ, Burnett JC: Activation of cardiorenal and pulmonary tissue endothelin-1 in experimental heart failure. Am J Physiol 2000;279:R974-R979
  47. Kobayashi T, Miyauchi T, Sakai S, Kobayashi M, Yamaguchi I, Goto K, Sugishita Y: Expression of endothelin-1, ETA and ETB receptors and ECE and distribution of endothelin-1 in failing rat heart. Am J Physiol 1999;276:H1197-H1206
  48. Liu J-L, Pliquett RU, Brewer E, Cornish KG, Shen Y-T, Zucker IH: Chronic endothelin-1 blockade reduces sympathetic nerve activity in rabbits with heart failure. Am J Physiol 2001;280:R1960-1913

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