Abstract: PO2462
Key Role for EphB2 Receptor in Kidney Fibrosis
Session Information
- CKD: Inflammation, Endothelial Dysfunction, and Signaling
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Huang, Zhimin, University of Utah Health, Salt Lake City, Utah, United States
- Liu, Simeng, University of Utah Health, Salt Lake City, Utah, United States
- Tang, Anna, University of Utah Health, Salt Lake City, Utah, United States
- Huang, Yufeng, University of Utah Health, Salt Lake City, Utah, United States
Background
Eph-Ephrin receptor-ligand signaling has been implicated in the development of tissue fibrosis, though it has not been well defined in the kidney.
Methods
We then firstly made use of male EphB2-knockout and littermate control mice (n=5/per group) to receive unilateral renal ischemia-reperfusion (IR) surgery for 35min. In addition, EphB2 signaling was further determined in varied kidney disease models, particullary in diabetes- or hypertension-induced kidney disease models and in the kidney biopsy tissue from IgA nephropathy with glomerulosclerosis and tubular fibrosis.
Results
We detected substantial upregulation of expression and phosphorylation of the EphB2 receptor tyrosine kinase in fibrotic kidney tissue obtained both from mice subjected to either the unilateral renal IR model at 14 days or type 2 diabates or DOCA & Ang II-infused hypertension and in patients suffering from chronic kidney disease (CKD). Knockout mice lacking EphB2 expression exhibited a normal renal structure and function, indicating no major role for this receptor in kidney development or action. Although IR injury is well known to cause tissue damage, fibrosis, and renal dysfunction, we found that kidneys from EphB2 knockout mice showed much less renal tubular injury and retained a more preserved renal function. IR-injured kidneys from EphB2 knockouts exhibited greatly reduced fibrosis and inflammation compared to injured wild-type (WT) littermates, and this correlated with a significant reduction in renal expression of pro-fibrotic molecules, inflammatory cytokines, NADPH oxidases, and markers for cell proliferation, tubular epithelial-to-mesenchymal transition, myofibroblast activation, and apoptosis. A panel of 760 fibrosis-associated genes were further assessed, revealing that 506 genes in WT mouse kidney following IR injury changed their expression. However, 70.9% of those genes were back to or close to normal in expression when EphB2 was deleted.
Conclusion
These data indicate endogenous EphB2 expression and signaling are abnormally activated after kidney injury and subsequently contributes to the development of renal fibrosis via regulation of multiple pro-fibrotic pathways.
Funding
- NIDDK Support