Rac1 activation in podocytes induces rapid foot process effacement and proteinuria.
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.
Department of Pathology and Immunology.
Haiyang
H
Yu
Hani
H
Suleiman
Alfred H J
AH
Kim
Jeffrey H
JH
Miner
Adish
A
Dani
Andrey S
AS
Shaw
Shreeram
S
Akilesh
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007678:Kidney Glomerulus / Q000201:enzymology / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000378:metabolism*; D050199:Podocytes / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011507:Proteinuria / Q000201:enzymology* / Q000473:pathology; D059748:Proteolysis; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C113267:nephrin; D046988:Proteasome Endopeptidase Complex; D020830:rac1 GTP-Binding Protein