Podocyte-specific deletion of dicer alters cytoskeletal dynamics and causes glomerular disease.
MicroRNAs (miRNAs) regulate gene expression by binding the 3' untranslated region of mRNAs. To define their role in glomerular function, miRNA biogenesis was disrupted in mouse podocytes using a conditional Dicer allele. Mutant mice developed proteinuria by 3 wk after birth and progressed rapidly to end-stage kidney disease. Podocyte pathology included effacement, vacuolization, and hypertrophy with crescent formation. Despite normal expression of WT1, podocytes underwent dedifferentiation, exemplified by cytoskeletal disruption with early transcriptional downregulation of synaptopodin. These abnormalities differed from Cd2ap(-/-) mice, indicating they were not a general consequence of glomerular disease. Glomerular labeling of ezrin, moesin, and gelsolin was altered at 3 wk, but expression of nestin and alpha-actinin was unchanged. Abnormal cell proliferation or apoptosis was not responsible for the glomerular injury. Mutant podocytes were incapable of synthesizing mature miRNA, as revealed by their loss of miR-30a. In contrast, expression of glomerular endothelial and mesangial cell miRNAs (miR-126 and miR-145, respectively) was unchanged. These findings demonstrate a critical role for miRNA in glomerular function and suggest a pathway that may participate in the pathogenesis of kidney diseases of podocyte origin. The unique architecture of podocytes may make them especially susceptible to cytoskeletal alterations initiated by aberrant miRNA dynamics.
Harvey
Scott J
SJ
Renal Division, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jarad
George
G
Cunningham
Jeanette
J
Goldberg
Seth
S
Schermer
Bernhard
B
Harfe
Brian D
BD
McManus
Michael T
MT
Benzing
Thomas
T
Miner
Jeffrey H
JH
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D003599:Cytoskeleton / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004722:Endoribonucleases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D050199:Podocytes / Q000201:enzymology* / Q000473:pathology; D012323:RNA Processing, Post-Transcriptional; D043244:Ribonuclease III
D035683:MicroRNAs; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
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