Podocyte-specific Loss of Functional MicroRNAs Leads to Rapid Glomerular and Tubular Injury

Overview

Journal J Am Soc Nephrol

Specialty Nephrology

Date 2008 Oct 4

PMID 18832437

Citations 153

Authors

Jacqueline Ho

Kar Hui Ng

Seymour Rosen

Ales Dostal

Richard I Gregory

Jordan A Kreidberg

Affiliations

Soon will be listed here.

Abstract

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.

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References

Wang Y, Medvid R, Melton C, Jaenisch R, Blelloch R . DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nat Genet. 2007; 39(3):380-5. PMC: 3008549. DOI: 10.1038/ng1969. View

Pfaffl M, Horgan G, Dempfle L . Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 2002; 30(9):e36. PMC: 113859. DOI: 10.1093/nar/30.9.e36. View

Hammond S . Dicing and slicing: the core machinery of the RNA interference pathway. FEBS Lett. 2005; 579(26):5822-9. DOI: 10.1016/j.febslet.2005.08.079. View

Wang Q, Huang Z, Xue H, Jin C, Ju X, Han J . MicroRNA miR-24 inhibits erythropoiesis by targeting activin type I receptor ALK4. Blood. 2007; 111(2):588-95. DOI: 10.1182/blood-2007-05-092718. View

Rajewsky N . microRNA target predictions in animals. Nat Genet. 2006; 38 Suppl:S8-13. DOI: 10.1038/ng1798. View

Koop K, Eikmans M, Baelde H, Kawachi H, de Heer E, Paul L . Expression of podocyte-associated molecules in acquired human kidney diseases. J Am Soc Nephrol. 2003; 14(8):2063-71. DOI: 10.1097/01.asn.0000078803.53165.c9. View

Kloosterman W, Wienholds E, de Bruijn E, Kauppinen S, Plasterk R . In situ detection of miRNAs in animal embryos using LNA-modified oligonucleotide probes. Nat Methods. 2005; 3(1):27-9. DOI: 10.1038/nmeth843. View

Harfe B, McManus M, Mansfield J, Hornstein E, Tabin C . The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. Proc Natl Acad Sci U S A. 2005; 102(31):10898-903. PMC: 1182454. DOI: 10.1073/pnas.0504834102. View

Schmittgen T, Lee E, Jiang J, Sarkar A, Yang L, Elton T . Real-time PCR quantification of precursor and mature microRNA. Methods. 2007; 44(1):31-8. PMC: 2663046. DOI: 10.1016/j.ymeth.2007.09.006. View

10.

Doublier S, Ruotsalainen V, Salvidio G, Lupia E, Biancone L, Conaldi P . Nephrin redistribution on podocytes is a potential mechanism for proteinuria in patients with primary acquired nephrotic syndrome. Am J Pathol. 2001; 158(5):1723-31. PMC: 1891937. DOI: 10.1016/S0002-9440(10)64128-4. View

11.

ORourke J, Georges S, Seay H, Tapscott S, McManus M, Goldhamer D . Essential role for Dicer during skeletal muscle development. Dev Biol. 2007; 311(2):359-68. PMC: 2753295. DOI: 10.1016/j.ydbio.2007.08.032. View

12.

Chen L, Al-Awqati Q . Segmental expression of Notch and Hairy genes in nephrogenesis. Am J Physiol Renal Physiol. 2005; 288(5):F939-52. DOI: 10.1152/ajprenal.00369.2004. View

13.

Williams A, Moschos S, Perry M, Barnes P, Lindsay M . Maternally imprinted microRNAs are differentially expressed during mouse and human lung development. Dev Dyn. 2006; 236(2):572-80. PMC: 2582151. DOI: 10.1002/dvdy.21047. View

14.

Castoldi M, Benes V, Hentze M, Muckenthaler M . miChip: a microarray platform for expression profiling of microRNAs based on locked nucleic acid (LNA) oligonucleotide capture probes. Methods. 2007; 43(2):146-52. DOI: 10.1016/j.ymeth.2007.04.009. View

15.

Piscione T, Wu M, Quaggin S . Expression of Hairy/Enhancer of Split genes, Hes1 and Hes5, during murine nephron morphogenesis. Gene Expr Patterns. 2004; 4(6):707-11. DOI: 10.1016/j.modgep.2004.04.007. View

16.

Wienholds E, Kloosterman W, Miska E, Alvarez-Saavedra E, Berezikov E, de Bruijn E . MicroRNA expression in zebrafish embryonic development. Science. 2005; 309(5732):310-1. DOI: 10.1126/science.1114519. View

17.

Obernosterer G, Martinez J, Alenius M . Locked nucleic acid-based in situ detection of microRNAs in mouse tissue sections. Nat Protoc. 2007; 2(6):1508-14. DOI: 10.1038/nprot.2007.153. View

18.

Castoldi M, Schmidt S, Benes V, Noerholm M, Kulozik A, Hentze M . A sensitive array for microRNA expression profiling (miChip) based on locked nucleic acids (LNA). RNA. 2006; 12(5):913-20. PMC: 1440900. DOI: 10.1261/rna.2332406. View

19.

Grimson A, Farh K, Johnston W, Garrett-Engele P, Lim L, Bartel D . MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007; 27(1):91-105. PMC: 3800283. DOI: 10.1016/j.molcel.2007.06.017. View

20.

Takemoto M, Asker N, Gerhardt H, Lundkvist A, Johansson B, Saito Y . A new method for large scale isolation of kidney glomeruli from mice. Am J Pathol. 2002; 161(3):799-805. PMC: 1867262. DOI: 10.1016/S0002-9440(10)64239-3. View