Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

MicroRNAs as mediators and therapeutic targets in chronic kidney disease

Nature Reviews Nephrology volume 7, pages 286–294 (2011)Cite this article

Subjects

Abstract

Chronic kidney disease (CKD) is characterized by tubulointerstitial deposition of extracellular matrix, tubular atrophy and dilatation; the replacement of organ architecture by connective tissue results in progressive loss of organ function. Micro (mi)RNAs are important mediators of tissue fibrosis under various pathological conditions and are of potential therapeutic relevance. These short, noncoding nucleotides (∼22 bases) regulate target messenger RNAs at the post-transcriptional level. Several hundred miRNAs regulate a considerable amount of the human genome and are involved in virtually all biological processes, including cellular proliferation, apoptosis and differentiation. Thus, miRNA deregulation often results in impaired cellular function and development of disease. Here, we summarize the current knowledge on the role of miRNAs in CKD, with particular emphasis on hypertensive kidney disease, diabetic nephropathy, glomerular biology, and IgA nephropathy. Identification of miRNA regulation and function in renal pathology may pinpoint miRNAs as new therapeutic targets in kidney fibrosis and related diseases. A new class of RNA therapeutics, that is, miRNA modulators (such as antagomirs) have been developed, which enable specific targeting of miRNAs and respective downstream gene networks in vivo, thus influencing the mechanisms that underlie disease initiation or progression. The therapeutic potential of miRNA-based treatment strategies in CKD are discussed.

Key Points

  • Chronic kidney diseases are associated with the development of tubulointerstitial fibrosis, which leads to progressive loss of organ function

  • Micro (mi)RNAs are endogenous, single-stranded short RNA molecules that regulate approximately 50% of the genome

  • miRNAs are deregulated in kidney diseases and influence the development of kidney fibrosis and dysfunction

  • Development of miRNA-based therapeutic strategies may attenuate or even reverse kidney fibrosis and dysfunction

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Biogenesis, mechanism of action and potential therapeutic utility of miRNAs.
Figure 2: Glomerular architecture under normal physiological conditions and chronic nephropathy.
Figure 3: The kidney can be targeted by chemically engineered miRNA antagonists (antagomirs).

Similar content being viewed by others

References

  1. Eddy, A. A. Molecular basis of renal fibrosis. Pediatr. Nephrol. 15, 290–301 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Boor, P., Ostendorf, T. & Floege, J. Renal fibrosis: novel insights into mechanisms and therapeutic targets. Nat. Rev. Nephrol. 6, 643–656 (2010).

    Article  PubMed  Google Scholar 

  3. Foley, R. N., Parfrey, P. S. & Sarnak, M. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am. J. Kidney Dis. 32, 112–119 (1998).

    Article  Google Scholar 

  4. Kumar, V., Abbas, A. K. & Fausto, N. Pathologic Basis of Disease 87–118 (Elsevier Saunders, Philadelphia, 2005).

    Google Scholar 

  5. Quan, T. E., Cowper, S. E. & Bucala, R. The role of circulating fibrocytes in fibrosis. Curr. Rheumatol. Rep. 8, 145–150 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Willis, B. C., du Bois, R. M. & Borok, Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc. Am. Thorac. Soc. 3, 377–382 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kalluri, R. & Neilson, E. G. Epithelial–mesenchymal transition and its implications for fibrosis. J. Clin. Invest. 112, 1776–1784 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bucala, R., Spiegel, L. A., Chesney, J., Hogan, M. & Cerami, A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol. Med. 1, 71–81 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zeisberg, E. M., Potenta, S. E., Sugimoto, H., Zeisberg, M. & Kalluri, R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J. Am. Soc. Nephrol. 19, 2282–2287 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Humphreys, B. D. et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am. J. Pathol. 176, 85–97 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zeisberg, M. & Duffield, J. S. Resolved: EMT produces fibroblasts in the kidney. J. Am. Soc. Nephrol. 21, 1247–1253 (2010).

    Article  PubMed  Google Scholar 

  12. van Rooij, E. et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc. Natl Acad. Sci. USA 105, 13027–13032 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Thum, T. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980–984 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Liu, G. et al. MiR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J. Exp. Med. 207, 1589–1597 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Thum, T. et al. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation 116, 258–267 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. MicroCosm Targets, Version 5. EMBL–EBI database [online], (2010).

  18. Chiang, H. R. et al. Mammalian microRNAs: experimental evaluation of novel and previously annotated genes. Genes Dev. 24, 992–1009 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cai, X., Hagedorn, C. H. & Cullen, B. R. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 10, 1957–1966 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee, Y. et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23, 4051–4060 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lee, Y. et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415–419 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Gregory, R. I. et al. The microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Valencia-Sanchez, M. A., Liu, J., Hannon, G. J. & Parker, R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 20, 515–524 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    CAS  PubMed  Google Scholar 

  26. Guo, H., Ingolia, N. T., Weissman, J. S. & Bartel, D. P. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466, 835–840 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Harvey, J. M. et al. Renal biopsy findings in hypertensive patients with proteinuria. Lancet 340, 1435–1356 (1992).

    Article  CAS  PubMed  Google Scholar 

  28. Zucchelli, P. & Zuccalà, A. Primary hypertension—how does it cause renal failure? Nephrol. Dial. Transplant. 9, 223–225 (1994).

    CAS  PubMed  Google Scholar 

  29. Marcantoni, C., Ma, L. J., Federspiel, C. & Fogo, A. B. Hypertensive nephrosclerosis in African Americans versus Caucasians. Kidney Int. 62, 172–180 (2002).

    Article  PubMed  Google Scholar 

  30. Kincaid-Smith, P. Hypothesis: obesity and the insulin resistance syndrome play a major role in end-stage renal failure attributed to hypertension and labelled 'hypertensive nephrosclerosis'. J. Hypertens. 22, 1051–1055 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Sequeira López, M. L., Pentz, E. S., Nomasa, T., Smithies, O. & Gomez, R. A. Renin cells are precursors for multiple cell types that switch to the renin phenotype when homeostasis is threatened. Dev. Cell. 6, 719–728 (2004).

    Article  PubMed  Google Scholar 

  32. Sequeira-López, M. L. et al. The microRNA-processing enzyme dicer maintains juxtaglomerular cells. J. Am. Soc. Nephrol. 21, 460–467 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Wang, G. et al. Intrarenal expression of miRNAs in patients with hypertensive nephrosclerosis. Am. J. Hypertens. 23, 78–84 (2010).

    Article  PubMed  Google Scholar 

  34. Tian, Z., Greene, A. S., Pietrusz, J. L., Matus, I. R. & Liang, M. MicroRNA-target pairs in the rat kidney identified by microRNA microarray, proteomic, and bioinformatic analysis. Genome Res. 18, 404–411. (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sun, Y. et al. Development of a micro-array to detect human and mouse microRNAs and characterization of expression in human organs. Nucleic Acids Res. 32, e188 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Bracken, C. P. et al. A double-negative feedback loop between ZEB1–SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 68, 7846–7854 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Paterson, E. L. et al. The microRNA-200 family regulates epithelial to mesenchymal transition. ScientificWorldJournal 8, 901–904 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Liu, Y. et al. Renal medullary microRNAs in Dahl salt-sensitive rats: miR-29b regulates several collagens and related genes. Hypertension 55, 974–982 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Fiedler, J., Gupta, S. & Thum, T. Micro-RNA based therapeutic approaches in the cardiovascular system. Cardiovasc. Ther. doi:10.1111/j.1755–5922.2010.00220.x.

  40. Fioretto, P., Steffes, M. W., Brown, D. M. & Mauer, S. M. An overview of renal pathology in insulin-dependent diabetes mellitus in relationship to altered glomerular hemodynamics. Am. J. Kidney Dis. 20, 549–558 (1992).

    Article  CAS  PubMed  Google Scholar 

  41. Adler, S. Diabetic nephropathy: linking histology, cell biology, and genetics. Kidney Int. 66, 2095–2106 (2004).

    Article  PubMed  Google Scholar 

  42. Susztak, K., Raff, A. C., Schiffer, M. & Bottinger, E. P. Glucose induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55, 225–233 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Krupa, A. et al. Loss of microRNA-192 promotes fibrogenesis in diabetic nephropathy. J. Am. Soc. Nephrol. 21, 438–447 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu, Y. Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J. Am. Soc. Nephrol. 15, 1–12 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Comijn, J. et al. The two-handed E-box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol. Cell 7, 1267–1278 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Kato, M. et al. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-β-induced collagen expression via inhibition of E-box repressors. Proc. Natl Acad. Sci. USA 104, 3432–3427 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kato, M. et al. TGF-β activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN. Nat. Cell. Biol. 11, 881–889 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jiang, B. H. & Liu, L. Z. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv. Cancer Res. 102, 19–65 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Suzuki, A., Nakano, T., Mak, T. W. & Sasaki, T. Portrait of PTEN: messages from mutant mice. Cancer Sci. 99, 209–213 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Chung, A. C., Huang, X. R., Meng, X. & Lan, H. Y. miR-192 mediates TGF-β/Smad3-driven renal fibrosis. J. Am. Soc. Nephrol. 21, 1317–1325 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang, B. et al. E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of TGFβ. Diabetes 59, 1794–1802 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Du, B. et al. High glucose down-regulates miR-29a to increase collagen IV production in HK-2 cells. FEBS Lett. 584, 811–816 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Wang, Q. et al. MicroRNA-377 is up-regulated and can lead to increased fibronectin production in diabetic nephropathy. FASEB J. 22, 4126–4135 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fleissner, F. et al. Asymmetric dimethylarginine impairs angiogenic progenitor cell function in patients with coronary artery disease through a microRNA-21-dependent mechanism. Circ. Res. 107, 138–143 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Shi, S. et al. Podocyte-selective deletion of dicer induces proteinuria and glomerulosclerosis. J. Am. Soc. Nephrol. 19, 2159–2169 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang, G. et al. Intrarenal expression of microRNAs in patients with IgA nephropathy. Lab. Invest. 90, 98–103 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Krützfeldt, J. et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature 438, 685–689 (2005).

    Article  PubMed  Google Scholar 

  58. Lanford, R. E. et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327, 198–201 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Patrick, D. M. et al. Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice. J. Clin. Invest. 120, 3912–3916 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Thum, T. et al. Comparison of different miR-21 inhibitor chemistries in a cardiac disease model. J. Clin. Invest. 121, 461–462 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kim, V. N. MicroRNA biogenesis: coordinated cropping and dicing. Nat. Rev. Mol. Cell. Biol. 6, 376–385 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Ebert, M. S. et al. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat. Methods 4, 721–726 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Xiao, J. et al. Novel approaches for gene-specific interference via manipulating actions of microRNAs: examination on the pacemaker channel genes HCN2 and HCN4. J. Cell. Physiol. 212, 285–292 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Sayed, D. et al. MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths. Mol. Biol. Cell. 19, 3272–3282 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Krützfeldt, J. et al. Specificity, duplex degradation and subcellular localization of antagomirs. Nucl. Acids Res. 35, 2885–2892 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Martinez, J., Patkaniowska, A., Urlaub, H., Luhrmann, R. & Tuschl, T. Singlestranded antisense siRNAs guide target RNA cleavage in RNAi. Cell 110, 563–574 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Jazbutyte, V. & Thum, T. MicroRNA-21: from cancer to cardiovascular disease. Curr. Drug Targets 11, 926–935 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover, 30625, Germany

    Johan M. Lorenzen & Thomas Thum

  2. Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover, 30625, Germany

    Hermann Haller

Authors
  1. Johan M. Lorenzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hermann Haller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Thum
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J. M. Lorenzen and T. Thum made equal contributions to researching data for the article and to writing the article. H. Haller provided substantial discussion of the content. J. M. Lorenzen, H. Haller and T. Thum contributed equally to reviewing and editing the manuscript.

Corresponding author

Correspondence to Thomas Thum.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lorenzen, J., Haller, H. & Thum, T. MicroRNAs as mediators and therapeutic targets in chronic kidney disease. Nat Rev Nephrol 7, 286–294 (2011). https://doi.org/10.1038/nrneph.2011.26

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2011.26

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research