Rac1 activation in podocytes induces the spectrum of nephrotic syndrome
Richard Robins1, Cindy Baldwin1, Lamine Aoudjit1
1Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada.
Abstract:
Hyper-activation of Rac1, a small GTPase, in glomerular podocytes has been implicated in the pathogenesis of familial proteinuric kidney diseases. However, the role of Rac1 in acquired nephrotic syndrome is unknown. To gain direct insights into this, we generated a transgenic mouse model expressing a doxycycline-inducible constitutively active form of Rac1 (CA-Rac1) in podocytes. Regardless of the copy number, proteinuria occurred rapidly within five days, and the histology resembled minimal change disease. The degree and severity of proteinuria were dependent on the transgene copy number. Upon doxycycline withdrawal, proteinuria resolved completely (one copy) or nearly completely (two copy). After one month of doxycycline treatment, two-copy mice developed glomerulosclerosis that resembled focal segmental glomerulosclerosis (FSGS) with urinary shedding of transgene-expressing podocytes. p38 MAPK was activated in podocytes upon CA-Rac1 induction while a p38 inhibitor attenuated proteinuria, podocyte loss, and glomerulosclerosis. Mechanistically, activation of Rac1 in cultured mouse podocytes reduced adhesiveness to laminin and induced redistribution of β1 integrin, and both were partially reversed by the p38 inhibitor. Activation of Rac1 in podocytes was also seen in kidney biopsies from patients with minimal change disease and idiopathic FSGS by immunofluorescence while sera from the same patients activated Rac1 in cultured human podocytes. Thus, activation of Rac1 in podocytes causes a spectrum of disease ranging from minimal change disease to FSGS, due to podocyte detachment from the glomerular basement membrane that is partially dependent on p38 MAPK.
Insights
Hyper-activation of Rac1 in kidney podocytes causes proteinuric kidney diseases, ranging from minimal change disease to focal segmental glomerulosclerosis (FSGS). This process involves podocyte detachment and is partly mediated by p38 MAPK.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Hyper-activation of Rac1, a small GTPase, in glomerular podocytes is linked to familial proteinuric kidney diseases.
- The specific role of Rac1 in acquired nephrotic syndrome remains unclear.
Purpose of the Study:
- To investigate the role of Rac1 in acquired nephrotic syndrome using a novel transgenic mouse model.
- To elucidate the mechanisms underlying Rac1-induced podocyte dysfunction and kidney disease.
Main Methods:
- Generation of a doxycycline-inducible constitutively active Rac1 (CA-Rac1) transgenic mouse model in podocytes.
- Induction of CA-Rac1 expression and assessment of proteinuria, kidney histology, and podocyte markers.
- In vitro studies using cultured podocytes and in vivo studies with a p38 MAPK inhibitor.
- Immunofluorescence analysis of kidney biopsies from patients with minimal change disease and FSGS.
Main Results:
- CA-Rac1 induction in podocytes rapidly caused proteinuria resembling minimal change disease, with severity dependent on transgene copy number.
- Proteinuria resolved upon doxycycline withdrawal, but prolonged induction led to glomerulosclerosis akin to FSGS and podocyte shedding.
- p38 MAPK activation was observed in podocytes upon CA-Rac1 induction; p38 inhibition attenuated proteinuria, podocyte loss, and glomerulosclerosis.
- Rac1 activation reduced podocyte adhesiveness to laminin and altered β1 integrin distribution, partially reversed by p38 inhibition.
- Rac1 activation in podocytes was detected in human kidney disease biopsies, and patient sera activated Rac1 in cultured human podocytes.
Conclusions:
- Rac1 hyper-activation in podocytes drives a spectrum of kidney diseases from minimal change disease to FSGS.
- Podocyte detachment from the glomerular basement membrane, partly mediated by p38 MAPK, is a key mechanism.
- These findings highlight Rac1 as a potential therapeutic target in acquired proteinuric kidney diseases.
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