A microRNA checkpoint for Ca2+ signaling and overload in acute pancreatitis

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.