A microRNA checkpoint for Ca 2+ signaling and overload in acute pancreatitis

Mol Ther. 2022 Apr 6;30(4):1754-1774. doi: 10.1016/j.ymthe.2022.01.033. Epub 2022 Jan 22.

Abstract

Acute pancreatitis (AP) is a common digestive disease without specific treatment, and its pathogenesis features multiple deleterious amplification loops dependent on translation, triggered by cytosolic Ca2+ ([Ca2+]i) overload; however, the underlying mechanisms in Ca2+ overload of AP remains incompletely understood. Here we show that microRNA-26a (miR-26a) inhibits pancreatic acinar cell (PAC) store-operated Ca2+ entry (SOCE) channel expression, Ca2+ overload, and AP. We find that major SOCE channels are post-transcriptionally induced in PACs during AP, whereas miR-26a expression is reduced in experimental and human AP and correlated with AP severity. Mechanistically, miR-26a simultaneously targets Trpc3 and Trpc6 SOCE channels and attenuates physiological oscillations and pathological elevations of [Ca2+]i in PACs. MiR-26a deficiency increases SOCE channel expression and [Ca2+]i overload, and significantly exacerbates AP. Conversely, global or PAC-specific overexpression of miR-26a in mice ameliorates pancreatic edema, neutrophil infiltration, acinar necrosis, and systemic inflammation, accompanied with remarkable improvements on pathological determinants related with [Ca2+]i overload. Moreover, pancreatic or systemic administration of an miR-26a mimic to mice significantly alleviates experimental AP. These findings reveal a previously unknown mechanism underlying AP pathogenesis, establish a critical role for miR-26a in Ca2+ signaling in the exocrine pancreas, and identify a potential target for the treatment of AP.

Keywords: autophagy; endoplasmic reticulum stress; inflammation; mouse models; noncoding RNA; pancreatic acinar cell; store-operated calcium entry channels; targeted therapy; transient receptor potential canonical channels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinar Cells / metabolism
  • Acute Disease
  • Animals
  • Calcium / metabolism
  • Calcium Signaling
  • Humans
  • Mice
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Pancreatitis* / genetics
  • Pancreatitis* / metabolism
  • Pancreatitis* / pathology

Substances

  • MicroRNAs
  • Calcium