Abstract: FR-PO1077
Hyaluronan Synthase Contributes to Tubulointerstitial Fibrosis in a Murine Model of CKD
Session Information
- CKD Mechanisms: Progression, Fibrosis, and Beyond
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Yung, Susan, Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong, Hong Kong
- Xu, Yuesong, Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong, Hong Kong
- Garcia Cordoba, Cristina Alexandra, Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong, Hong Kong
- Chan, Tak Mao Daniel, Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong, Hong Kong
Background
Chronic kidney disease (CKD) is characterized by progressive tubulointerstitial fibrosis and tubular atrophy, leading to kidney failure. There is currently no effective treatment for CKD. Understanding the mechanisms that mediate tubulointerstitial fibrosis is prerequisite for the development of novel treatment options. Hyaluronan (HA) is a ubiquitous component of the extracellular matrix and has pleiotropic functions depending on its molecular weight. High molecular weight HA is generated by HA synthase (HAS) I and II and possesses anti-inflammatory and anti-fibrotic properties, whereas low molecular weight HA is synthesized by HAS III and contributes to inflammatory and fibrotic processes. We investigated the role of HAS I, II and III in tubulointerstitial inflammation and fibrosis in CKD.
Methods
CKD was induced in wild-type (WT) and HAS I, III or I/III-knockout (KO) mice by feeding with 0.2% adenine in casein-based chow for 8 weeks after which time, mice were sacrificed and kidneys harvested and assessed for histopathological changes. Twenty-four hour urine was collected to determine proteinuria. WT and KO mice fed with casein-based chow served as non-CKD controls.
Results
Tubulointerstitial HA expression was increased in WT CKD mice compared with non-CKD WT controls and this was accompanied by development of proteinuria, tubular atrophy, infiltration of immune cells, and increased collagen and α-smooth muscle actin expression. HAS I, III and I/III KO mice with CKD showed less severe histopathological abnormalities with decreased expression of mediators of fibrosis and reduced immune cell infiltration, the latter being more pronounced in HAS I KO mice, compared to WT CKD mice. Moreover, HAS I and HAS III KO, but not HAS I/III KO mice with CKD showed a significant reduction in proteinuria compared to WT CKD mice (P<0.05, for both).
Conclusion
Our data suggest that HAS I, II and III have distinct contribution to kidney function deterioration and tubulointerstitial inflammation and fibrosis in murine adenine-induced CKD.
Funding
- Government Support – Non-U.S.