TRPV1 activation stimulates NKCC1 and increases hydrostatic pressure in the mouse lens

Mohammad Shahidullah, Amritlal Mandal, Richard T. Mathias, Junyuan Gao, David Križaj, Sarah Redmon, Nicholas A. Delamere

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Shahidullah M, Mandal A, Mathias RT, Gao J, Križaj D, Redmon S, Delamere NA. TRPV1 activation stimulates NKCC1 and increases hydrostatic pressure in the mouse lens. Am J Physiol Cell Physiol 318: C969–C980, 2020. First published April 15, 2020; doi:10.1152/ajpcell.00391.2019.—The porcine lens response to a hyperosmotic stimulus involves an increase in the activity of an ion cotransporter sodium-potassium/two-chloride cotransporter 1 (NKCC1). Recent studies with agonists and antagonists pointed to a mechanism that appears to depend on activation of transient receptor potential vanilloid 1 (TRPV1) ion channels. Here, we compare responses in lenses and cultured lens epithelium obtained from TRPV1-/- and wild type (WT) mice. Hydrostatic pressure (HP) in lens surface cells was determined using a manometer-coupled microelectrode approach. The TRPV1 agonist capsaicin (100 nM) caused a transient HP increase in WT lenses that peaked after ~30 min and then returned toward baseline. Capsaicin did not cause a detectable change of HP in TRPV1-/- lenses. The NKCC inhibitor bumetanide prevented the HP response to capsaicin in WT lenses. Potassium transport was examined by measuring Rb+ uptake. Capsaicin increased Rb+ uptake in cultured WT lens epithelial cells but not in TRPV1-/- cells. Bumetanide, A889425, and the Akt inhibitor Akti prevented the Rb+ uptake response to capsaicin. The bumetanide-sensitive (NKCC-dependent) component of Rb+ uptake more than doubled in response to capsaicin. Capsaicin also elicited rapid (<2 min) NKCC1 phosphorylation in WT but not TRPV1-/- cells. HP recovery was shown to be absent in TRPV1-/- lenses exposed to hyperosmotic solution. Bumetanide and Akti prevented HP recovery in WT lenses exposed to hyperosmotic solution. Taken together, responses to capsaicin and hyperosmotic solution point to a functional role for TRPV1 channels in mouse lens. Lack of NKCC1 phosphorylation and Rb+ uptake responses in TRPV1-/- mouse epithelium reinforces the notion that a hyperosmotic challenge causes TRPV1-dependent NKCC1 activation. The results are consistent with a role for the TRPV1-activated signaling pathway leading to NKCC1 stimulation in lens osmotic homeostasis.

Original languageEnglish (US)
Pages (from-to)C969-C980
JournalAmerican Journal of Physiology - Cell Physiology
Issue number5
StatePublished - May 2020


  • Hydrostatic pressure
  • Knockout
  • Lens
  • NKCC
  • TRPV1

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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