Rac1 Activation in Podocytes Induces Rapid Foot Process Effacement and Proteinuria

Abstract

The kidney's vital filtration function depends on the structural integrity of the glomerulus, the proximal portion of the nephron. Within the glomerulus, the architecturally complex podocyte forms the final cellular barrier to filtration. Injury to the podocyte results in a morphological change called foot process effacement, which is a ubiquitous feature of proteinuric diseases. The exact mechanism underlying foot process effacement is not known, but recently it has been proposed that this change might reflect activation of the Rac1 GTPase. To test this hypothesis, we generated a podocyte-specific, inducible transgenic mouse line that expressed constitutively active Rac1. When the Rac1 transgene was induced, we observed a rapid onset of proteinuria with focal foot process effacement. Using superresolution imaging, we verified that the induced transgene was expressed in damaged podocytes with altered foot process morphology. This work sheds new light on the complex balance of Rho GTPase signaling that is required for proper regulation of the podocyte cytoskeleton.

TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1

“…Previous work on RAC1 in kidney disease has focused on its role in the podocyte, where unrestrained activation of RAC1 leads to podocyte effacement and proteinuria (65)(66)(67)(68) and kidney fibrosis, whereby RAC1 alters macrophage migration (69). In contrast, the role of RAC1 in AKI has received little attention.…”

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

“…5). Although hyperactivation of Rac1 is an accepted pathogenetic model in podocyte disease verified by several independent studies (40,41), there is an ambiguous perception regarding the role of RhoA. Nevertheless, an emerging body of evidence supports the concept of a required balance of these GTPases to maintain cellular function (42).…”

Albumin-associated free fatty acids induce macropinocytosis in podocytes

“…We and others have previously shown that RAC1 activation in podocytes leads to podocyte foot process effacement and proteinuria in mice (49,50). In addition, excessive macropinocytosis and accumulation of albumin in podocytes has been shown to induce lysosomal dysfunction, podocyte loss, and subsequent glomerulo- sclerosis (15,16,(51)(52)(53)(54)(55).…”