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Abstract: TH-PO081

Role of Interleukin-4 Receptor-JAK3-STAT6 Signaling in the AKI-to-CKD transition

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Barrera-Chimal, Jonatan, UNAM, Instituto de Investigaciones Biomedicas - Instituto Nacional de Cardiologia, Ignacio Chavez, Mexico City, Mexico
  • Estrela, Gabriel R., INSERM U1138 - Centre de Recherche des Cordeliers, Paris, France
  • El moghrabi, Soumaya, INSERM U1138 - Centre de Recherche des Cordeliers, Paris, France
  • Kolkhof, Peter, BAYER AG, Wuppertal, Germany
  • Jaisser, Frederic, INSERM U1138 - Centre de Recherche des Cordeliers, Paris, France

Mineralocorticoid receptor (MR) antagonism is highly efficient to prevent both acute injury and the progression to chronic kidney disease (CKD) after an ischemic episode by enhancing a macrophage M2 polarization in the early post-ischemic phase and might be therefore an efficient repair mechanism. Interleukin-4 (IL-4) receptor activation in myeloid cells appears to be part of the protective mechanism. The exact contribution of IL-4 receptor downstream signaling potentially through JAK3-STAT6 in renal protection mediated by finerenone remains unclear. We tested the involvement of IL-4 receptor signaling induced by MR inhibition in the development of kidney fibrosis after an ischemic acute kidney injury (AKI) episode.


Thirty male C57/B6 mice were divided in: sham, renal ischemia for 22.5 min (IR), IR plus treatment with the non-steroidal MR antagonist finerenone (10 mg/kg) at -48, -24 and -1 h before IR and two groups of mice subjected to IR and receiving finerenone plus a STAT6 or JAK3 inhibitor. The mice were followed-up during 4 weeks to test for AKI to CKD transition. In another set of mice, the macrophages were sorted from kidneys after 24 h of reperfusion and flow cytometry characterization was performed.


The progression of AKI to CKD after 4 weeks of renal ischemia in the untreated mice was characterized by a 40% increase in plasma creatinine, a 6-fold increase in proteinuria, severe tubule-interstitial fibrosis and increased mRNA levels of NGAL, Kim-1, alpha-SMA, fibronectin, TGF-beta and collagen-I. The mice that received finerenone were protected against all these alterations. MR inhibition promoted increased IL-4 receptor expression and phosphorylation in the whole kidney and in isolated macrophages. The protective effect conferred by MR antagonism was partially reversed by STAT6 inhibition as evidenced by a 5-fold increase in proteinuria and by the JAK3 inhibitor which partially reversed the tubule-interstitial fibrosis protection, and completely prevented the reduction in Kim-1 and fibrosis related gene expression.


Finerenone modulates the IL-4 receptor-JAK3-STAT6 signaling pathway, leading to macrophage phenotype switching and protection against AKI to CKD transition.


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