A novel role of BK potassium channel activity in preventing the development of kidney fibrosis

Kidney Int. 2022 May;101(5):945-962. doi: 10.1016/j.kint.2021.11.033. Epub 2021 Dec 27.

Abstract

Kidney fibrosis is a common characteristic of chronic kidney disease and while the large conductance voltage and calcium-activated potassium channel (BK) is widely expressed in kidneys, its role in kidney fibrosis is unknown. To evaluate this, we found that BK protein expression was decreased in the fibrotic kidneys. Accompanying this was increased fibrotic marker protein expression of fibronectin, vimentin and α-smooth muscle actin and increased mRNA expressions of fibronectin, α-smooth muscle actin, collagen III and collagen I. These changes occurred in the unilateral ureteral obstruction and folic acid models of fibrosis and were more pronounced in BK knockout than in wild-type mice. Activation of BK activity by chemical NS1619 or BMS191011 channel openers attenuated kidney fibrosis in these two models while protecting kidney function in wild-type mice. BK deficiency up-regulated transforming growth factor-β (TGF-β)/transcription factor Smad2/3 signaling in the fibrotic kidney, whereas activation of BK activity inhibited this signaling pathway both in vivo and in vitro. BK channel activation increased the degradation of TGF-β receptors induced by TGF-β1 in vivo and in vitro. Furthermore, in cell lines HK-2, NRK49, and NRK-52E, BK channel activation by NS1619 led to increased caveolae formation and facilitated localization of TGF-β receptors in the microdomains of lipid rafts. Thus, our data demonstrated that BK activation has an anti-fibrotic effect on kidney fibrosis by inhibiting the TGF-β signaling pathway through accelerating TGF-β receptor degradation via the caveolae route. Hence, our study provides innovative insight into BK as a potential therapeutic target for the treatment of kidney fibrosis.

Keywords: TGF- β; chronic kidney disease; fibrosis; potassium channel.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Collagen / metabolism
  • Female
  • Fibronectins / metabolism
  • Fibrosis
  • Humans
  • Kidney / pathology
  • Kidney Diseases* / etiology
  • Kidney Diseases* / metabolism
  • Kidney Diseases* / prevention & control
  • Large-Conductance Calcium-Activated Potassium Channels / metabolism
  • Male
  • Mice
  • Potassium / metabolism
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction
  • Transforming Growth Factor beta1 / metabolism
  • Ureteral Obstruction* / metabolism

Substances

  • Actins
  • Fibronectins
  • Large-Conductance Calcium-Activated Potassium Channels
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Collagen
  • Potassium