Abstract: TH-PO043
Injured Tubules-Derived CCN1 Exacerbates Renal Congestion-Mediated AKI and Fibrosis
Session Information
- AKI: Epidemiology, Risk Factors, and Prevention - 1
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 101 AKI: Epidemiology, Risk Factors, and Prevention
Authors
- Minamida, Atsushi, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Kusaba, Tetsuro, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Nakata, Tomohiro, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Kirita, Yuhei, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Tamagaki, Keiichi, Kyoto Prefectural University of Medicine, Kyoto, Japan
Background
In recent studies on cardio-renal syndrome (CRS), researchers have focused on the relationship between increased renal venous pressure and renal dysfunction. We generated a novel mouse model where the inferior vena cava between the left and right renal vein was constricted, causing renal congestion only in the left kidney (Kidney Int. 2022). However, the responsible molecular mechanisms for congestion-mediated acceleration of kidney fibrosis after injury are still unclear. We found thatCellular Communication Network Factor 1 (CCN1) which is upregulated at the acute phase after kidney injury contributed to the fibroblast mobilization to the injury site. On this basis, we investigated the impact of CCN1 on the exacerbation of AKI caused by renal congestion with using proximal tubule-specific CCN1-KO mice (SLC34a1GCE/CCN1-floxed).
Methods
We performed bilateral ischemia-reperfusion injury (IRI) and unilateral renal congestion in wild-type (WT) mice and proximal tubule-specific CCN1-KO mice. Furthermore, we analyzed the role of CCN1 on the fibroblasts, tubular epithelial cells, and macrophages in vitro.
Results
One day after the injury, qPCR analysis of WT mice revealed a significant increase in CCN1 levels in the congestion-IRI group compared to the IRI group, but no difference in renal injury markers between those. Positive staining of phosphorylated focal adhesion kinase (pFAK), a downstream signaling of CCN1, was observed in the fibroblasts at injury sites in the congestion-IRI kidneys. Seven days after the injury, qPCR and histological analyses showed a significant increase in fibrosis markers in the congestion-IRI group. In vitro, CCN1 activated the phosphorylation of FAK and ERK, resulting in the acceleration of migration in the fibroblasts (NRK49F) and macrophages, but not in tubular epithelia. Lastly, we examined the effect of CCN1 deletion in tubular epithelia on congestion-mediated kidney injury in vivo. pFAK expression in injury sites was reduced in CCN1-KO mice, and tissue fibrosis was significantly ameliorated.
Conclusion
We clarified the important role of injured tubular-derived CCN1 on pFAK-mediated fibroblast migration in congestive kidneys. Inhibition of CCN1 can be an attractive therapeutic candidate for preventing renal congestion-mediated kidney injury to fibrosis transition.