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2016 ; 310
(8
): F777-F784
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Dosage-dependent role of Rac1 in podocyte injury
#MMPMID26792065
Wan X
; Lee MS
; Zhou W
Am J Physiol Renal Physiol
2016[Apr]; 310
(8
): F777-F784
PMID26792065
show ga
Activation of small GTPase Rac1 in podocytes is associated with rodent models of
kidney injury and familial nephrotic syndrome. Induced Rac1 activation in
podocytes in transgenic mice results in rapid transient proteinuria and foot
process effacement, but not glomerular sclerosis. Thus it remains an open
question whether abnormal activation of Rac1 in podocytes is sufficient to cause
permanent podocyte damage. Using a number of transgenic zebrafish models, we
showed that moderate elevation of Rac1 activity in podocytes did not impair the
glomerular filtration barrier but aggravated metronidazole-induced podocyte
injury, while inhibition of Rac1 activity ameliorated metronidazole-induced
podocyte injury. Furthermore, a further increase in Rac1 activity in podocytes
was sufficient to cause proteinuria and foot process effacement, which resulted
in edema and lethality in juvenile zebrafish. We also found that activation of
Rac1 in podocytes significantly downregulated the expression of nephrin and
podocin, suggesting an adverse effect of Rac1 on slit diaphragm protein
expression. Taken together, our data have demonstrated a causal link between
excessive Rac1 activity and podocyte injury in a dosage-dependent manner, and
transgenic zebrafish of variable Rac1 activities in podocytes may serve as useful
animal models for the study of Rac1-related podocytopathy.
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