Activation of RhoA in podocytes induces focal segmental glomerulosclerosis.

Proper organization of the actin cytoskeleton is essential for the normal structure and function of podocytes. RhoA modulates actin dynamics but its role in podocyte biology is controversial. Here, we generated transgenic mice that express a constitutively active form of RhoA in a podocyte-specific and doxycycline-inducible manner. Induction of activated RhoA with doxycycline resulted in significant albuminuria. Furthermore, both the degree of albuminuria and the histologic changes in the glomerulus positively correlated with the level of constitutively active RhoA expression: low levels of expression associated with segmental foot-process effacement without changes observable by light microscopy, whereas higher levels of expression associated with both extensive foot-process effacement and histologic features of focal segmental glomerulosclerosis (FSGS). In addition, induction of activated RhoA markedly upregulated glomerular mRNA expression of fibronectin and collagen IA1, and the degree of upregulation positively correlated with the level of albuminuria. Withdrawal of doxycycline led to a decline in albuminuria toward basal levels in most mice, but heavy albuminuria persisted in some mice. Taken together, these data suggest that activation of RhoA in podocytes leads to albuminuria accompanied by a range of histologic changes characteristic of minimal change disease and FSGS in humans. Although most changes are reversible, severe and prolonged activation of RhoA may cause irreversible glomerulosclerosis.