Kidney Week

Abstract: FR-OR43

CTGF Aggravates the Oxidative Stress-DNA Damage-Cellular Senescence Sequence Following Renal Ischemia-Reperfusion Injury

Session Information

• Molecular Pathology, Pathogenesis, and Animal Models: A Correlative Approach to Kidney Diseases
  November 05, 2021 | Location: Simulive, Virtual Only
  Abstract Time: 04:30 PM - 06:00 PM

Category: Pathology and Lab Medicine

• 1600 Pathology and Lab Medicine

Authors

• Valentijn, Floris, Universitair Medisch Centrum Utrecht Afdeling Pathologie, Utrecht, Utrecht, Netherlands

Floris Valentijn, MD

• Knoppert, Sebastiaan, Universitair Medisch Centrum Utrecht Afdeling Pathologie, Utrecht, Utrecht, Netherlands

Sebastiaan Knoppert,

• Kester, Lennart, Universitair Medisch Centrum Utrecht Afdeling Pathologie, Utrecht, Utrecht, Netherlands

Lennart Kester,

• Rodrigues díez, Raúl R., Hospital Universitario Fundacion Jimenez Diaz, Madrid, Madrid, Spain

Raúl R. Rodrigues díez,

• Marquez-Exposito, Laura, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Madrid, Spain

Laura Marquez-Exposito,

• Broekhuizen, Roel, Universitair Medisch Centrum Utrecht Afdeling Pathologie, Utrecht, Utrecht, Netherlands

Roel Broekhuizen,

• Goldschmeding, Roel, Universitair Medisch Centrum Utrecht Afdeling Pathologie, Utrecht, Utrecht, Netherlands

Roel Goldschmeding,

• Ruiz-Ortega, Marta, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Madrid, Spain

Marta Ruiz-Ortega,

• Nguyen, Tri Q., Universitair Medisch Centrum Utrecht Afdeling Pathologie, Utrecht, Utrecht, Netherlands

Tri Q. Nguyen,

• Falke, Lucas, Universitair Medisch Centrum Utrecht Afdeling Pathologie, Utrecht, Utrecht, Netherlands

Lucas Falke,

Background

Recent data suggest that AKI to CKD progression may be driven by cellular senescence evolving from prolonged DNA damage response following oxidative stress. Connective tissue growth factor (CTGF; CCN2) is a major contributor to CKD development and was found to aggravate DNA damage and the subsequent DNA damage response (DDR)-Cellular Senescence-Fibrosis sequence following renal ischemia reperfusion injury (IRI). Here, we investigated the impact of CTGF inhibition on the immediate (4 hours) and early (3 days) renal response to IRI.

Methods

We induced AKI by bilateral IRI in wild type and conditional CTGF-KO mice and euthanized the mice 4 hours and 3 days after reperfusion. We performed full transcriptome RNA sequencing to identify major dysregulated pathways and validated the findings by qPCR and immunohistochemistry.

Results

IRI resulted in upregulation of CTGF 4 hours and 3 days after reperfusion (Figure 1A,C).
Four hours after reperfusion, CTGF-dependent differentially regulated genes were enriched in multiple signaling pathways related to oxidative stress and DNA damage. Consistently, decreased staining for γH2AX and p-p53 (Figure 1B) indicated reduced DNA damage response in tubular epithelial cells of CTGF-KO mice, although decline in kidney function, acute tubular damage score, and KIM1- and NGAL expression were not different.
Three days after IRI, oxidative stress response markers (4HNE, nitrotyrosine, and Nrf2 target genes HMOX1 and NQO1), DDR markers (γH2AX-, p-p53, p21), and anti-apoptotic factors (Bcl-xL, HMGB1) were less elevated in CTGF-KO than in wild type mice.

Conclusion

Together, our observations suggest that CTGF inhibition might mitigate AKI to CKD progression by reducing oxidative stress induced DNA damage and the subsequent DDR-cellular senescence-fibrosis sequence response.