Abstract: TH-PO341

Tubular BMPR1A-SMAD1/5/8-ID Signaling Mediates Renal Recovery via Inhibition of Profibrotic Processes after Ischemia-Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 002 AKI: Repair and Regeneration

Authors

  • Vigolo, Emilia, Max Delbrueck Center for Molecular Medicine, Berlin, Germany
  • Marko, Lajos, Experimental and Clinical Research Center, Berlin, Germany
  • Hinze, Christian, Max Delbrueck Center for Molecular Medicine, Berlin, Germany
  • Müller, Dominik N., Max Delbrueck Center for Molecular Medicine, Berlin, Germany
  • Schmidt-ullrich, Ruth, Max Delbrueck Center for Molecular Medicine, Berlin, Germany
  • Schmidt-Ott, Kai M., Max Delbrueck Center for Molecular Medicine, Berlin, Germany
Background

The signaling pathways that mediate renal recovery after acute kidney injury (AKI) constitute potential targets of pharmacologic intervention. Bone morphogenetic protein (BMP) signaling has been previously implicated in preventing profibrotic responses in the injured kidney, but its detailed role and molecular targets after AKI are incompletely understood. We therefore addressed the time course, molecular targets and cellular functions of BMP signaling after experimental AKI.

Methods

A unilateral ischemia reperfusion injury (IRI) mouse model was used to investigate renal regeneration. The modulation of BMP signaling after IRI was monitored in kidney tissue by examined the nuclear expression pattern of phosphorylated BMP-specific transcription factors SMAD1/5/8 (pSMAD1/5/8) using immunostaining and Western blotting. To study the role of BMP signaling in tubules, we generated a tubular-specific and injury-dependent BMP type 1A receptor (BMPR1A) knock-out (Bmpr1a cKO) mouse model. Tubular injury and inflammation were evaluated by renal histology, and immunostaining for infiltrating neutrophils and macrophages. Tubulointerstitial fibrosis was examined by Masson’s trichrome staining and collagen IV Western blotting. pSMAD1/5/8 chromatin immunoprecipitation (ChIP-) and RNA-sequencing were performed to discover novel BMP targets during renal recovery.

Results

We observed that BMP signaling was transiently down-regulated during early injury phases and re-activated 7 days (d) after IRI, when the kidney is undergoing recovery. However, the Bmpr1a cKO kidneys failed to re-activate pSMAD1/5/8 and displayed an aggravated tubular injury and increased inflammation when compared to controls. 21 d after IRI the Bmpr1a cKO kidneys presented enhanced tubulointerstitial fibrosis. Comparative analyses between ChIP- and RNA-sequencing data revealed genes encoding inhibitor of DNA-binding (ID) proteins Id1, Id2, and Id4 as direct targets of BMP signaling during regeneration. Down-regulation of Id genes in Bmpr1a cKO kidneys was associated with activation of profibrotic factors, including P38 mitogen-activated kinase (MAPK), P21 and P27.

Conclusion

Successful recovery after ischemia-induced AKI is mediated by BMPR1A-SMAD1/5/8-ID signaling that prevents activation of profibrotic pathways.