Abstract: SA-PO107
Hypoxia Induces Pro-Regenerative Activity of Renal Fibroblasts via Hif1α
Session Information
- AKI: Mechanisms - III
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Zeisberg, Michael, University of Goettingen Medical Center, Goettingen, Germany
- Nyamsuren, Gunsmaa, University of Goettingen Medical Center, Goettingen, Germany
Background
Fibroblasts are the prototypical cells of connective tissue. In the kidney they are known to be the main mediators of fibrosis. It is often overlooked that renal fibroblasts have important physiological functions, such as control of regeneration from acute damage and the synthesis of erythropoietin. Recent studies demonstrated that acute kidney injury is associated with transient accumulation of activated fibroblasts, which aid regeneration of the injured tubular epithelium. Increased expression of growth factors by activated fibroblasts such as VEGF and FGF4 suggests that fibroblasts aid repair of the injured tubular epithelium through paracrine mechanisms. This study aimed to gain additional insight into the contribution of FGF4 to kidney regeneration and the underlying mechanisms.
Methods
Ischemia-reperfusion injury was induced by clamping of the of the left kidney pedicle for 45 min.
For reporter assays full length human FGF4 promoter DNA from -650 to +886
bp including three hypoxia response elementswere cloned into pGL4.10 luciferase reporter plasmid and subjected to site-directed mutagenesis.
Results
We report that acute ischemic kidney injury in mice and in humans was associated with increased expression of FGF4 by interstitial cells and with increased expression of FGF-receptors by tubular epithelial cells. Conditional ablation of FGF4 or administration of FGF4-neutralizing antibodies blunted renal regeneration upon ischemia-reperfusion injury.Cultivation of normal human kidney fibroblasts under hypoxic condidtions induced FGF4 expression. Overexpression of a dominant-negative Hif1α-mutant blunted FGF4 expression in response to hypoxia, whereas hypoxia-independent intracellular accumulation of Hif1α under normoxic conditions through its superphysiologic transgenic overexpression induced FGF4 transcription. Use of an FGF4 reporter construct in which hypoxia response elements (HREs) had been mutated further confirmed that hypoxia induces FGF4 expression in renal fibroblasts in Hif1α-dependent manner.
Conclusion
Our studies provide evidence that fibroblast aid in the repair of acute kidney injury through secretion of growth factors such as FGF4. Our studies further demonstrate that FGF4 expression is induced in response to hypoxia via Hif1α, suggesting that modulation of Hif1α responses may be an attractive therapeutic target to enhance renal regeneration.
Funding
- NIDDK Support