Kidney Week

Abstract: FR-PO972

CTGF/CCN2 Knockdown Prevents AKI-Induced Cellular Senescence and Subsequent Fibrosis

Session Information

• Pathology and Lab Medicine: Basic
  November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

• 1601 Pathology and Lab Medicine: Basic

Authors

• Valentijn, Floris, University Medical Center Utrecht, Utrecht, Netherlands

Floris Valentijn,

• Marquez-Exposito, Laura, IIS Fundacion Jimenez Diaz, Madrid, Spain

Laura Marquez-Exposito,

• Knoppert, Sebastiaan, University Medical Center Utrecht, Utrecht, Netherlands

Sebastiaan Knoppert,

• Rodrigues díez, Raúl R., Universidad Autonoma, Madrid, Spain

Raúl R. Rodrigues díez,

• Broekhuizen, Roel, University Medical Center Utrecht, Utrecht, Netherlands

Roel Broekhuizen,

• Leask, Andrew, University of Western Ontario, London, Ontario, Canada

Andrew Leask,

• Goldschmeding, Roel, University Medical Center Utrecht, Utrecht, Netherlands

Roel Goldschmeding,

• Nguyen, Tri Q., University Medical Center Utrecht, Utrecht, Netherlands

Tri Q. Nguyen,

• Ruiz-Ortega, Marta, Universidad Autonoma, Madrid, Spain

Marta Ruiz-Ortega,

• Falke, Lucas, University Medical Center Utrecht, Utrecht, Netherlands

Lucas Falke,

Group or Team Name

• Renal Pathology UMCU

Background

Acute kidney injury (AKI) involves damage to the tubular epithelium with subsequent accumulation of senescent cells and can progress to fibrosis and chronic kidney disease (CKD). Cellular senescence is characterized by anti-apoptotic and DNA Damage Response (DDR) features, and expression of a Senescence Associated Secretory Phenotype (SASP).
Connective Tissue Growth Factor (CTGF/CCN2) is a constituent of the SASP and has been implicated in fibrosis as well as in (paracrine) senescence induction. Therefore we explored the involvement of CTGF and cellular senescence in two models of AKI and subsequent CKD development.

Methods

We subjected wild type (WT) and conditional tamoxifen inducible CTGF-KO mice (CTGF-cKO) to bilateral ischemia reperfusion injury (IRI) and to folic acid (FA) renal injury and studied damage parameters in relation to anti-apoptotic signaling and cellular senescence in the acute and chronic phase of both models.

Results

In WT mice, both IRI and FA induced AKI resulted in upregulation of DDR and anti-apoptosis markers, including yH2Ax, p21^CIP1 (p21) and the BCL-2 family members BCL-xL and MCL-1. This effect persisted largely in the chronic phase, during which also the expression of p16^INK4a together with CTGF and other SASP factors like PAI-1, IL-1β, and IL-6 became markedly upregulated. Furthermore, CTGF expression levels correlated with senescence phenotype, including anti-apoptotic BCL-xL and MCL-1 in the acute phase, SASP factors like PAI-1, IL-1β and IL-6 in the chronic phase, and p21 in both phases.
CTGF knockdown protected against acute tubular injury and functional decline in the initial phase of both injury models. Furthermore, DDR- and anti-apoptotic marker expression (p21 and MCL-1) were lower in CTGF cKO than in WT mice. Likewise, in both models tubular atrophy, interstitial fibrosis and functional decline in the chronic phase were less severe in CTGF cKO mice, together with reduced expression of senescence (p21 and MCL-1) and SASP markers (PAI-1, IL-1β and IL-6).

Conclusion

CTGF/CCN2, beyond its known profibrotic role in CKD, is also involved in AKI , possibly by modulating apoptotic and cellular senescence associated pathways. We propose that inhibition of CTGF might be beneficial in AKI and diminish AKI to CKD progression.