Cyclosporine A-induced hypertension involves synapsin in renal sensory nerve endings

Weiguo Zhang, Jia Ling Li, Masahiro Hosaka, Roger Janz, John M. Shelton, George M. Albright, James A. Richardson, Thomas C. Südhof, Ronald G. Victor

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

The calcineurin inhibitor cyclosporine A (CsA) has emerged as a major cause of secondary hypertension in humans, but the underlying pathogenetic mechanisms have remained enigmatic. Synapsins are a family of synaptic vesicle phosphoproteins that are essential for normal regulation of neurotransmitter release at synapses. In addition to synaptic vesicles, synapsins and other vesicle proteins are found on microvesicles in sensory nerve endings in peripheral tissues. However, the functions of the sensory microvesicles in general, and of synapsins in particular, are unknown. We now demonstrate in a mouse model that CsA raises blood pressure by stimulating renal sensory nerve endings that contain synapsin-positive microvesicles. In knockout mice lacking synapsin I and II, sensory nerve endings are normally developed but not stimulated by CsA whereas a control stimulus, capsaicin, is fully active. The reflex activation of efferent sympathetic nerve activity and the increase in blood pressure by CsA seen in control are greatly attenuated in synapsin-deficient mice. These results provide a mechanistic explanation for CsA-induced acute hypertension and suggest that synapsins could serve as a drug target in this refractory condition. Furthermore, these data establish evidence that synapsin-containing sensory microvesicles perform an essential role in sensory transduction and suggest a role for synapsin phosphorylation in this process.

Original languageEnglish (US)
Pages (from-to)9765-9770
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number17
StatePublished - Aug 15 2000

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Synapsins
Sensory Receptor Cells
Cyclosporine
Hypertension
Kidney
Synaptic Vesicles
Blood Pressure
Phosphoproteins
Capsaicin
Knockout Mice
Synapses
Neurotransmitter Agents
Reflex
Phosphorylation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Zhang, W., Li, J. L., Hosaka, M., Janz, R., Shelton, J. M., Albright, G. M., ... Victor, R. G. (2000). Cyclosporine A-induced hypertension involves synapsin in renal sensory nerve endings. Proceedings of the National Academy of Sciences of the United States of America, 97(17), 9765-9770.

Cyclosporine A-induced hypertension involves synapsin in renal sensory nerve endings. / Zhang, Weiguo; Li, Jia Ling; Hosaka, Masahiro; Janz, Roger; Shelton, John M.; Albright, George M.; Richardson, James A.; Südhof, Thomas C.; Victor, Ronald G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 17, 15.08.2000, p. 9765-9770.

Research output: Contribution to journalArticle

Zhang, W, Li, JL, Hosaka, M, Janz, R, Shelton, JM, Albright, GM, Richardson, JA, Südhof, TC & Victor, RG 2000, 'Cyclosporine A-induced hypertension involves synapsin in renal sensory nerve endings', Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 17, pp. 9765-9770.
Zhang, Weiguo ; Li, Jia Ling ; Hosaka, Masahiro ; Janz, Roger ; Shelton, John M. ; Albright, George M. ; Richardson, James A. ; Südhof, Thomas C. ; Victor, Ronald G. / Cyclosporine A-induced hypertension involves synapsin in renal sensory nerve endings. In: Proceedings of the National Academy of Sciences of the United States of America. 2000 ; Vol. 97, No. 17. pp. 9765-9770.
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