Permselective dysfunction of podocyte-podocyte contact upon angiotensin II unravels the molecular target for renoprotective intervention.
Ameliorating the function of the glomerular barrier to circulating proteins by blocking angiotensin II (Ang II) translates into less risk of progression toward end-stage renal failure in diabetic and nondiabetic nephropathies. However, the mechanisms underlying this barrier protection are not clear. Specialized contacts between adjacent podocytes are major candidate targets, and the actin cytoskeleton is emerging as a regulatory element. Here, we present data demonstrating that Ang II induced reorganization of F-actin fibers and redistribution of zonula occludens-1 (ZO-1) that is physically associated with actin in murine podocytes. These effects were paralleled by increased albumin permeability across podocyte monolayers. The F-actin stabilizer jasplakinolide prevented both ZO-1 redistribution and albumin leakage, suggesting that actin cytoskeleton rearrangement is instrumental to podocyte permselective dysfunction induced by Ang II. Changes in both F-actin and ZO-1 patterns were confirmed in glomeruli of rat isolated perfused kidneys on short infusion of Ang II, leading to increased protein excretion. Podocyte dysfunction was mediated by Ang II type 1 receptor and was partly dependent on Src kinase-phospholipase C activation. These data demonstrate that strategies aimed at stabilizing podocyte-podocyte contacts and targeting the relevant intracellular signal transduction are crucial to renoprotection.
"Mario Negri" Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. macconi@marionegri.it
Daniela
D
Macconi
Mauro
M
Abbate
Marina
M
Morigi
Stefania
S
Angioletti
Marilena
M
Mister
Simona
S
Buelli
Maria
M
Bonomelli
Peter
P
Mundel
Karlhans
K
Endlich
Andrea
A
Remuzzi
Giuseppe
G
Remuzzi
D000199:Actins / Q000502:physiology; D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology; D047630:Depsipeptides / Q000494:pharmacology; D004789:Enzyme Activation; D066298:In Vitro Techniques; D007365:Intercellular Junctions / Q000502:physiology*; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D010539:Permeability; D010750:Phosphoproteins / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D012710:Serum Albumin, Bovine / Q000378:metabolism; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism; D062826:Zonula Occludens-1 Protein; D019061:src-Family Kinases / Q000378:metabolism
D000199:Actins; D047630:Depsipeptides; D008565:Membrane Proteins; D010750:Phosphoproteins; D044140:Receptor, Angiotensin, Type 1; C569043:Tjp1 protein, mouse; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; C057531:jasplakinolide; D000804:Angiotensin II; D012710:Serum Albumin, Bovine; D019061:src-Family Kinases; D010738:Type C Phospholipases