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β1-Integrin blockade prevents podocyte injury in experimental models of minimal change disease
Gabriel Cara-Fuentes1, Rakesh Verma1, Madhusudan Venkatareddy1
1Children's Hospital, CO, United States.
Introduction:
Activation of the focal adhesion kinase (FAK) in podocytes is involved in the pathogenesis of minimal change disease (MCD), but the pathway leading to its activation in this disease is unknown. Here, we tested whether podocyte β1 integrin is the upstream modulator of FAK activation and podocyte injury in experimental models of MCD-like injury.
Methods:
We used lipopolysaccharide (LPS) and MCD sera to induce MCD-like changes in vivo and in cultured human podocytes, respectively. We performed functional studies using specific β1 integrin inhibitors in vivo and in vitro, and integrated histological analysis, western blotting, and immunofluorescence to assess for morphological and molecular changes in podocytes. By ELISA, we measured serum LPS levels in 35 children with MCD or presumed MCD (idiopathic nephrotic syndrome [INS]) and in 18 healthy controls.
Results:
LPS-injected mice showed morphological (foot process effacement, and normal appearing glomeruli on light microscopy) and molecular features (synaptopodin loss, nephrin mislocalization, FAK phosphorylation) characteristic of human MCD. Administration of a β1 integrin inhibitor to mice abrogated FAK phosphorylation, and ameliorated proteinuria and podocyte injury following LPS. Children with MCD/INS in relapse had higher serum LPS levels than controls. In cultured human podocytes, β1 integrin blockade prevented cytoskeletal rearrangements following exposure to MCD sera in relapse.
Conclusions:
Podocyte β1 integrin activation is an upstream mediator of FAK phosphorylation and podocyte injury in models of MCD-like injury.
Insights
Podocyte beta1 integrin activation triggers focal adhesion kinase (FAK) phosphorylation, leading to podocyte injury in minimal change disease (MCD). Blocking beta1 integrin protects against MCD-like kidney injury.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Focal adhesion kinase (FAK) activation in podocytes contributes to minimal change disease (MCD) pathogenesis.
- The specific pathway activating FAK in MCD remains unclear.
Purpose of the Study:
- To investigate if podocyte beta1 integrin acts as an upstream regulator of FAK activation and podocyte injury in experimental MCD models.
Main Methods:
- MCD-like injury induced using lipopolysaccharide (LPS) in vivo and MCD sera in vitro.
- Functional studies with beta1 integrin inhibitors.
- Histological analysis, western blotting, and immunofluorescence.
- ELISA measurement of serum LPS levels in children with MCD/idiopathic nephrotic syndrome (INS) and controls.
Main Results:
- LPS-induced MCD models exhibited characteristic podocyte foot process effacement and molecular changes, including FAK phosphorylation.
- Beta1 integrin inhibition in mice reduced FAK phosphorylation, proteinuria, and podocyte injury.
- Children with active MCD/INS had elevated serum LPS levels.
- In vitro, beta1 integrin blockade prevented cytoskeletal changes in podocytes exposed to MCD sera.
Conclusions:
- Podocyte beta1 integrin activation is an upstream mediator of FAK phosphorylation and subsequent podocyte injury in MCD-like conditions.
