Meprin β expression modulates the interleukin-6 mediated JAK2-STAT3 signaling pathway in ischemia/reperfusion-induced kidney injury

Physiol Rep. 2022 Sep;10(18):e15468. doi: 10.14814/phy2.15468.


Meprin metalloproteinases have been implicated in the pathophysiology of ischemia/reperfusion (IR)-induced kidney injury. Previous in vitro data showed that meprin β proteolytically processes interleukin-6 (IL-6) resulting in its inactivation. Recently, meprin-β was also shown to cleave the IL-6 receptor. The goal of this study was to determine how meprin β expression impacts IL-6 and downstream modulators of the JAK2-STAT3-mediated signaling pathway in IR-induced kidney injury. IR was induced in 12-week-old male wild-type (WT) and meprin β knockout (βKO) mice and kidneys obtained at 24 h post-IR. Real-time PCR, western blot, and immunostaining/microscopy approaches were used to quantify mRNA and protein levels respectively, and immunofluorescence counterstaining with proximal tubule (PT) markers to determine protein localization. The mRNA levels for IL-6, CASP3 and BCL-2 increased significantly in both genotypes. Interestingly, western blot data showed increases in protein levels for IL-6, CASP3, and BCL-2 in the βKO but not in WT kidneys. However, immunohistochemical data showed increases in IL-6, CASP3, and BCL-2 proteins in select kidney tubules in both genotypes, shown to be PTs by immunofluorescence counterstaining. IR-induced increases in p-STAT-3 and p-JAK-2 in βKO at a global level but immunoflourescence counterstaining demonstrated p-JAK2 and p-STAT3 increases in select PT for both genotypes. BCL-2 increased only in the renal corpuscle of WT kidneys, suggesting a role for meprins expressed in leukocytes. Immunohistochemical analysis confirmed higher levels of leukocyte infiltration in WT kidneys when compared to βKO kidneys. The present data demonstrate that meprin β modulates IR-induced kidney injury in part via IL-6/JAK2/STAT3-mediated signaling.

Keywords: JAK2/STAT3 signaling; interleukin-6; ischemia/reperfusion; meprin β; metalloproteinase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Caspase 3 / metabolism
  • Interleukin-6* / metabolism
  • Ischemia / metabolism
  • Kidney / metabolism
  • Male
  • Metalloendopeptidases
  • Metalloproteases / metabolism
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-6 / metabolism
  • Reperfusion
  • Reperfusion Injury* / metabolism
  • Signal Transduction


  • Interleukin-6
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Receptors, Interleukin-6
  • Metalloproteases
  • Caspase 3
  • Metalloendopeptidases
  • meprin B