Podocyte-specific loss of functional microRNAs leads to rapid glomerular and tubular injury.
MicroRNAs (miRNAs) are in a class of endogenous, small, noncoding RNAs that exert their effects through posttranscriptional repression of specific target mRNAs. Although miRNAs have been implicated in the regulation of diverse biologic processes, little is known about miRNA function in the kidney. Here, mice lacking functional miRNAs in the developing podocyte were generated through podocyte-specific knockout of Dicer, an enzyme required for the production of mature miRNAs (Nphs2-Cre; Dicer(flx/flx)). Podocyte-specific loss of miRNAs resulted in significant proteinuria by 2 wk after birth, rapid progression of marked glomerular and tubular injury beginning at 3 wk, and death by 4 wk. Expression of the slit diaphragm proteins nephrin and podocin was decreased, and expression of the transcription factor WT1 was relatively unaffected. To identify miRNA-mRNA interactions that contribute to this phenotype, we profiled the glomerular expression of miRNAs; three miRNAs expressed in glomeruli were identified: mmu-miR-23b, mmu-miR-24, and mmu-miR-26a. These results suggest that miRNA function is dispensable for the initial development of glomeruli but is critical to maintain the glomerular filtration barrier.
Ho
Jacqueline
J
Department of Medicine, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
Ng
Kar Hui
KH
Rosen
Seymour
S
Dostal
Ales
A
Gregory
Richard I
RI
Kreidberg
Jordan A
JA
D000818:Animals; D001483:Base Sequence; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004722:Endoribonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D007678:Kidney Glomerulus / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D043244:Ribonuclease III
D017931:DNA Primers; D035683:MicroRNAs; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases