MicroRNA15a — A Molecule Modulating Multiple Pathologies in Diabetic Retinopathy

In this issue of EBioMedicine, Wang and colleagues have demonstrated an important role played by miR15 in diabetic retinopathy (Wang et al., 2016Wang Q. Navitskaya S. Chakravarthy H. et al.Dual anti-inflammatory and anti-angiogenic action of miR-15a in diabetic retinopathy.EBioMedicine. 2016; 11: 138-150Summary Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Using a large number of tools and state of the art technology they showed that in diabetes, miR-15a is reduced both in the bone marrow cells and in the retina. Inhibition of miR-15a upregulated acid sphingomyelinase (ASM), a pro-inflammatory molecule and vascular endothelial growth factor A, an angiogenic molecule expression in the retinal pigment epithelial cells and endothelial cells. Furthermore, migration and retinal vascular repair function was impaired in miR-15a inhibitor-treated circulating angiogenic cells. They further expanded the study to the animal model where they used mice with miR-15a overexpression using Tie-2 promoter. Diabetes induced increased retinal permeability was prevented in these mice. However, such miR-15a overexpression, although reduced ASM and VEGF-A expressions, didn't abolish it completely. MicroRNAs are increasingly being recognized as molecules with significant modulatory action, in multiple if not all biologic processes (Ghildiyal and Zamore, 2009Ghildiyal M. Zamore P.D. Small silencing RNAs: an expanding universe.Nat. Rev. Genet. 2009; 10: 94-108https://doi.org/10.1038/nrg2504Crossref PubMed Scopus (1830) Google Scholar). Hence, it is highly likely that they are also involved in disease processes and diabetic retinopathy is no exception. Here, this group with longstanding interest and expertise in diabetic retinopathy research demonstrated that miR15 is a potential drug target for the treatment of diabetic retinopathy (add Wang et al. ref.). In keeping with this research, previous studies from several groups including these investigators have demonstrated alterations of multiple microRNAs in chronic diabetic complications including diabetic retinopathy. The list include miR200b, miR146a, miR195 etc. (Feng et al., 2011Feng B. Chen S. McArthur K. Wu Y. Sen S. Ding Q. Feldman R.D. Chakrabarti S. miR-146a-mediated extracellular matrix protein production in chronic diabetes complications.Diabetes. 2011; 60: 2975-2984Crossref PubMed Scopus (166) Google Scholar, McArthur et al., 2011McArthur K. Feng B. Wu Y. Chen S. Chakrabarti S. MicroRNA-200b regulates vascular endothelial growth factor-mediated alterations in diabetic retinopathy.Diabetes. 2011; 60: 1314-1323Crossref PubMed Scopus (268) Google Scholar, Mortuza et al., 2014Mortuza R. Feng B. Chakrabarti S. miR-195 regulates SIRT1-mediated changes in diabetic retinopathy.Diabetologia. 2014; 57: 1037-1046https://doi.org/10.1007/s00125-014-3197-9Crossref PubMed Scopus (125) Google Scholar). However, in most of these publications, investigators used a particular miRNA to target a single mRNA. In this publication, Wang et al. used miR15a to demonstrate that it can be helpful in preventing multiple important biologic processes of significance in diabetic retinopathy, such as increased permeability and angiogenesis (mediated by VEGFA) and inflammatory cytokine production (mediated by ASM) (Penn et al., 2008Penn J.S. Madan A. Caldwell R.B. Bartoli M. Caldwell R.W. Hartnett M.E. Vascular endothelial growth factor in eye disease.Prog. Retin. Eye Res. 2008; 27: 331-371Crossref PubMed Scopus (522) Google Scholar, Yu et al., 2015Yu Y. Chen H. Su S.B. Neuroinflammatory responses in diabetic retinopathy.J. Neuroinflammation. 2015; 12: 141https://doi.org/10.1186/s12974-015-0368-7Crossref PubMed Scopus (68) Google Scholar). It is of further interest to note that bone marrow derived circulating angiogenic cells (CACs), which normally repairs endothelial injury, are unable to do such repair in diabetes (Kern and Grant, 2013Kern T.S. Grant M.B. Circulating mononuclear progenitor cells: differential roles for subpopulations in repair of retinal vascular injury.Invest. Ophthalmol. Vis. Sci. 2013; 54: 3000-3009Crossref PubMed Scopus (18) Google Scholar). However miR15a overexpression also corrected these derangements as demonstrated here. Interestingly, although miR15a directly targets VEGFA, its acts on the inflammatory mediators through ASM activation and ceramide production, which allowed it to regulate multiple pro-inflammatory transcripts. In addition, as noted, miR15a also regulates FGF-2. What role FGF-2 played in the context of current pathologies remains to be explored. There are additional important noteworthy points. Although both retinal pigment epithelial cells (RPE) and endothelial cells showed glucose induced reduction of miR15a and associated alteration, overexpression of miR15a in the endothelial cells (as Tie2 is not expressed in the RPE) prevented diabetes induced changes in the retina, further establishing the notion that retinal endothelial cells are the primary target of tissue damage in diabetes (Khan and Chakrabarti, 2007Khan Z.A. Chakrabarti S. Cellular signaling and potential new treatment targets in diabetic retinopathy.Exp. Diabetes Res. 2007; 31867https://doi.org/10.1155/2007/31867Crossref Scopus (76) Google Scholar). However, Tie-2 expressing circulating angiogenic cells (aka endothelial progenitor cells) also contributed to miR15a’s preventive effects on the retinal damage in diabetes. One of the main challenges in the micro RNAs based therapy is that one miRNA has multiple targets and one transcript is regulated post transcriptionally not only by multiple miRNAs, but also by other epigenetic phenomena including other non-coding RNAs, methylation etc. (Ghildiyal and Zamore, 2009Ghildiyal M. Zamore P.D. Small silencing RNAs: an expanding universe.Nat. Rev. Genet. 2009; 10: 94-108https://doi.org/10.1038/nrg2504Crossref PubMed Scopus (1830) Google Scholar, Ruiz et al., 2015Ruiz M.A. Feng B. Chakrabarti S. Polycomb repressive complex 2 regulates MiR-200b in retinal endothelial cells: potential relevance in diabetic retinopathy.PLoS One. 2015; 10:e0123987https://doi.org/10.1371/journal.pone.0123987Crossref Scopus (52) Google Scholar). Hence, further investigations related to miR15a's biogenesis and regulations in the context of diabetes are warranted. In some instances, where alterations of multiple molecules, controlled by one miRNA lead to pathogenesis of a disease, specific miRNA may lend itself to be a potential therapeutic target as shown in this paper. However, a large number of other transcripts are also regulated by miR15a (www.targetscan.org). Hence, other off-target actions may also potentially act as disease modifiers. Furthermore, long term effects of miR15a manipulation in any disease process as well as on other organs are not clear. Hence, long-term studies in larger animal models are needed to broaden our understanding of microRNA based therapy for a chronic disease such as diabetic retinopathy. Nevertheless the current research is an important step towards developing novel therapeutic approach for the treatment of diabetic retinopathy. From a mechanistic standpoint, it is important to understand these novel molecular regulations aimed towards the development of RNA based therapy for this disease. The author declared no conflicts of interest. Dual Anti-Inflammatory and Anti-Angiogenic Action of miR-15a in Diabetic RetinopathyActivation of pro-inflammatory and pro-angiogenic pathways in the retina and the bone marrow contributes to pathogenesis of diabetic retinopathy. We identified miR-15a as key regulator of both pro-inflammatory and pro-angiogenic pathways through direct binding and inhibition of the central enzyme in the sphingolipid metabolism, ASM, and the pro-angiogenic growth factor, VEGF-A. miR-15a was downregulated in diabetic retina and bone marrow cells. Over-expression of miR-15a downregulated, and inhibition of miR-15a upregulated ASM and VEGF-A expression in retinal cells. Full-Text PDF Open Access

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