Abstract: FR-PO176
Role of Versican in Cisplatin-Induced AKI to CKD Transition
Session Information
- AKI: Mechanisms
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Wang, Dan, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
- Arango Velasquez, Juan P., The Ohio State University, Columbus, Ohio, United States
- Zepeda-Orozco, Diana, Nationwide Children's Hospital, Columbus, Ohio, United States
- Madhavan, Sethu M., The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
- Parikh, Samir V., The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
- Pabla, Navjot, The Ohio State University, Columbus, Ohio, United States
- Ferrell, Nicholas J., The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
Background
Versican is an extracellular matrix (ECM) proteoglycan with five isoforms (V0-V4) that impacts immunity and inflammation. Studies have shown that versican is upregulated following injury in lung, heart and liver, and versican deficiency protects from acute lung injury. However, the role of versican in regulating renal response in AKI and AKI-CKD transition has not been studied. We hypothesize that versican plays a role in response to AKI and primes ECM for fibrosis in the setting of AKI-CKD transition.
Methods
Mass spectrometry data on human CKD biopsy samples were used to analyze the correlation between versican expression and interstitial fibrosis. We use two cisplatin-induced mouse models: AKI with single high-dose cisplatin (25mg/kg), and AKI-CKD where acute injury transitions to chronic injury and fibrosis with 2 low-doses (10 mg/kg) of cisplatin. C57BL/6J male mice (8-10 weeks) were euthanized 3 days, 2wks, or 1 month post-injection. Kidney tissues were collected and processed for histological analysis, immunofluorescence staining, and immunoblot and qPCR analysis of isoform specific versican expression. Marker of kidney injury (KIM-1 and NGAL) and fibrosis (tenacin C, periostin, aSMA, ACTA2, and col1a1) were evaluated by qPCR.
Results
Versican expression is upregulated in chronic injury and correlates strongly with the degree of interstitial fibrosis in human CKD. Gene expression for all kidney expressed isoforms of versican (V0, V1, V3, Vtotal) and protein expression are upregulated at 72 hours after AKI. In the setting of AKI-CKD transition, versican gene expression increases initially, peaks at 2wks, and then decreases but remains upregulated at 1 month after treatment. This indicates the kidney injury persists and transitions to chronic kidney damage. Gene expressions of fibrosis markers are upregulated in AKI-CKD model. This study shows that versican is rapidly upregulated following acute injury and persists during transition to CKD.
Conclusion
We show upregulation of versican mRNA and protein expression during AKI and AKI-CKD transition. Versican may play a role in ECM remodeling and progressive fibrosis during AKI-CKD transition. Future studies aim to determine the role of versican in promoting fibrogenesis during AKI-CKD transition.
Funding
- Other U.S. Government Support