Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury.

Publication Type:

Journal Article


Kidney Int, Volume 84, Issue 5, p.920-30 (2013)


Actin Depolymerizing Factors, Acute Kidney Injury, Albuminuria, Animals, asb, cdc42 GTP-Binding Protein, Cell Shape, Desoxycorticosterone Acetate, Disease Models, Animal, Genotype, Hypertension, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Nephrectomy, Neuropeptides, Phenotype, Phosphorylation, Podocytes, Protamines, rac1 GTP-Binding Protein, Renal Insufficiency, Signal Transduction, Time Factors


Podocytes are highly specialized epithelial cells with complex actin cytoskeletal architecture crucial for maintenance of the glomerular filtration barrier. The mammalian Rho GTPases Rac1 and Cdc42 are molecular switches that control many cellular processes, but are best known for their roles in the regulation of actin cytoskeleton dynamics. Here, we employed podocyte-specific Cre-lox technology and found that mice with deletion of Rac1 display normal podocyte morphology without glomerular dysfunction well into adulthood. Using the protamine sulfate model of acute podocyte injury, podocyte-specific deletion of Rac1 prevented foot process effacement. In a long-term model of chronic hypertensive glomerular damage, however, loss of Rac1 led to an exacerbation of albuminuria and glomerulosclerosis. In contrast, mice with podocyte-specific deletion of Cdc42 had severe proteinuria, podocyte foot process effacement, and glomerulosclerosis beginning as early as 10 days of age. In addition, slit diaphragm proteins nephrin and podocin were redistributed, and cofilin was dephosphorylated. Cdc42 is necessary for the maintenance of podocyte structure and function, but Rac1 is entirely dispensable in physiological steady state. However, Rac1 has either beneficial or deleterious effects depending on the context of podocyte impairment. Thus, our study highlights the divergent roles of Rac1 and Cdc42 function in podocyte maintenance and injury.