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TGF-β-induced signaling circuit loops mediated by microRNAs as new therapeutic targets for renal fibrosis?

2013; Elsevier BV; Volume: 84; Issue: 6 Linguagem: Inglês

10.1038/ki.2013.297

1523-1755

Mitsuo Kato,

Chronic Kidney Disease and Diabetes

MicroRNAs (miRNAs) are emerging molecules in the pathogenesis of human diseases. Identification of miRNAs related to renal fibrosis provides clues to find new signaling pathways to fill the gaps between signaling molecules. Li et al. report another new pathway mediated by miR-433 that is induced by transforming growth factor-β1 in mouse models of renal fibrosis. The signaling also makes a positive-feedback circuit loop, which could be translated into new therapeutic targets. MicroRNAs (miRNAs) are emerging molecules in the pathogenesis of human diseases. Identification of miRNAs related to renal fibrosis provides clues to find new signaling pathways to fill the gaps between signaling molecules. Li et al. report another new pathway mediated by miR-433 that is induced by transforming growth factor-β1 in mouse models of renal fibrosis. The signaling also makes a positive-feedback circuit loop, which could be translated into new therapeutic targets. End-stage renal failure is caused by progressive renal fibrosis, a common feature of chronic kidney diseases.1.Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics.Kidney Int. 2006; 69: 213-217Abstract Full Text Full Text PDF PubMed Scopus (890) Google Scholar,2.Kato M. Natarajan R. MicroRNA circuits in transforming growth factor-beta actions and diabetic nephropathy.Semin Nephrol. 2012; 32: 253-260Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Excessive deposition of extracellular matrix, such as collagens and fibronectin, is a major characteristic of renal fibrosis, and transforming growth factor-β1 (TGF-β1) is a key player in profibrotic events.1.Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics.Kidney Int. 2006; 69: 213-217Abstract Full Text Full Text PDF PubMed Scopus (890) Google Scholar,2.Kato M. Natarajan R. MicroRNA circuits in transforming growth factor-beta actions and diabetic nephropathy.Semin Nephrol. 2012; 32: 253-260Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Although many approaches have attempted to clarify the mechanisms related to kidney fibrosis induced by TGF-β, there are still unexplained gaps between signaling molecules. MicroRNAs (miRNAs), short non-coding RNAs (about 22 nucleotides), are recent players in the pathogenesis of human diseases, including renal fibrosis.2.Kato M. Natarajan R. MicroRNA circuits in transforming growth factor-beta actions and diabetic nephropathy.Semin Nephrol. 2012; 32: 253-260Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 3.Chandrasekaran K. Karolina D.S. Sepramaniam S. et al.Role of microRNAs in kidney homeostasis and disease.Kidney Int. 2012; 81: 617-627Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 4.Kasinath B.S. Feliers D. The complex world of kidney microRNAs.Kidney Int. 2011; 80: 334-337Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Usually miRNAs negatively regulate the expression of target genes through their 3′-untranslated region. Aberrant expression of miRNAs causes abnormal expression of target genes and eventually results in many kinds of diseases. Interestingly, the connections between miRNAs and their targets provide new pathways in signal transduction, since certain miRNAs sometimes fill the gaps between signaling molecules—for example, in extracellular matrix accumulation related to fibrosis by TGF-β or activation of Akt related to glomerular hypertrophy.2.Kato M. Natarajan R. MicroRNA circuits in transforming growth factor-beta actions and diabetic nephropathy.Semin Nephrol. 2012; 32: 253-260Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 3.Chandrasekaran K. Karolina D.S. Sepramaniam S. et al.Role of microRNAs in kidney homeostasis and disease.Kidney Int. 2012; 81: 617-627Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 4.Kasinath B.S. Feliers D. The complex world of kidney microRNAs.Kidney Int. 2011; 80: 334-337Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Li et al.5.Li R. Chung A.C.K. Dong Y. et al.The microRNA miR-433 promotes renal fibrosis by amplifying the TGF-β/Smad3-Azin1 pathway.Kidney Int. 2013; 84: 1129-1144Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar (this issue) now report another new miRNA-mediated pathway in TGF-β-induced renal fibrosis. Since their previous paper showed a significant increase of miR-433 in mouse kidneys after unilateral ureteral obstruction (UUO) for 5 days,6.Chung A.C. Huang X.R. Meng X. et al.miR-192 mediates TGF-beta/Smad3-driven renal fibrosis.J Am Soc Nephrol. 2010; 21: 1317-1325Crossref PubMed Scopus (309) Google Scholar they confirmed the increase of miR-433 in NRK-52E cells treated with TGF-β. miR-433 knock-down (KD) short hairpin RNA attenuated the increase of profibrotic genes such as collagens, fibronectin, and α-smooth muscle actin by TGF-β, and miR-433 overexpression enhanced the expression of these profibrotic genes, suggesting that miR-433 may mediate these TGF-β effects. In in vivo experiments, miR-433 KD plasmid also attenuated the increase of TGF-β and profibrotic gene expression and immunostaining of these profibrotic gene products in kidneys from UUO mice. Smad3 (a major mediator transcription factor of TGF-β signaling) binding elements (SBEs) were found in the miR-433 promoter and one of SBEs interacted with Smad3 in the response to TGF-β. The increase of miR-433 was not detected in Smad3 knockout (KO) mice even after UUO, strongly suggesting that Smad3 is a key mediator of miR-433 upregulation in renal fibrosis (Figure 1). Azin1 was identified as one of the targets of miR-433 by in silico search and confirmed as a direct target by 3′-untranslated region reporter assay. Azin1 expression was decreased in UUO mice and NRE-52E cells treated with TGF-β. Azin1 is known as an inhibitor of antizyme, which destroys ornithine decarboxylase, a critical enzyme for polyamine synthesis. Therefore, miR-433 increase by TGF-β eventually induces polyamine depletion, which creates positive feedback to TGF-β signaling in kidney cells, while it has been suggested that polyamine depletion enhances TGF-β signaling in other tissues.7.Liu L. Santora R. Rao J.N. et al.Activation of TGF-beta-Smad signaling pathway following polyamine depletion in intestinal epithelial cells.Am J Physiol Gastrointest Liver Physiol. 2003; 285: G1056-G1067Crossref PubMed Scopus (54) Google Scholar Therefore, TGF-β-induced signaling circuit loops mediated by miR-433 may amplify the signaling (Figure 1), as suggested also in other animal CKD models.2.Kato M. Natarajan R. MicroRNA circuits in transforming growth factor-beta actions and diabetic nephropathy.Semin Nephrol. 2012; 32: 253-260Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 8.Deshpande S.D. Putta S. Wang M. et al.Transforming growth factor-β induced cross talk between p53 and a microRNA in the pathogenesis of diabetic nephropathy.Diabetes. 2013; 62: 3151-3162Crossref PubMed Scopus (140) Google Scholar, 9.Kato M. Arce L. Wang M. et al.A microRNA circuit mediates transforming growth factor-beta1 autoregulation in renal glomerular mesangial cells.Kidney Int. 2011; 80: 358-368Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 10.Kato M. Dang V. Wang M. et al.TGF-beta induces acetylation of chromatin and of Ets-1 to alleviate repression of miR-192 in diabetic nephropathy.Sci Signal. 2013; 6 ([online]): ra43Crossref PubMed Scopus (110) Google Scholar The chronic states of signal activation can be caused by continuous activation of the same signaling and can be the cause of chronic disease, such as renal fibrosis. An obvious next question is how to stop these signaling circuits in diseased animals. Li et al. tried several ways to stop this circuit, using miR-433 KD plasmid, Azin1 overexpression plasmid, and antizyme small interfering RNA (siRNA).5.Li R. Chung A.C.K. Dong Y. et al.The microRNA miR-433 promotes renal fibrosis by amplifying the TGF-β/Smad3-Azin1 pathway.Kidney Int. 2013; 84: 1129-1144Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar These three approaches were successful in inhibiting the profibrotic gene expression in NRE-52E cells treated with TGF-β. More interestingly, the delivery of miR-433 KD plasmid into UUO mice using the ultrasound technique reduced renal fibrosis in vivo. These results give us some hope to prevent renal fibrosis by inhibiting miRNAs. Despite this elegant work by Li et al., some questions still remain. (1) Is miR-433 involved in human patients? Since Li et al. showed that the miR-433 expression was upregulated in other animal models of renal fibrosis (anti-GBM nephritis and adriamycin nephropathy),5.Li R. Chung A.C.K. Dong Y. et al.The microRNA miR-433 promotes renal fibrosis by amplifying the TGF-β/Smad3-Azin1 pathway.Kidney Int. 2013; 84: 1129-1144Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar miR-433 seems involved in at least rodent models of renal fibrosis. (2) Is miR-433 useful as a biomarker of renal fibrosis? Recently, circulating miRNAs (in blood or body fluids) or urinary miRNAs have been suggested as biomarkers for human diseases.2.Kato M. Natarajan R. MicroRNA circuits in transforming growth factor-beta actions and diabetic nephropathy.Semin Nephrol. 2012; 32: 253-260Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar,11.Cai X. Xia Z. Zhang C. et al.Serum microRNAs levels in primary focal segmental glomerulosclerosis.Pediatr Nephrol. 2013; 28: 1797-1801Crossref PubMed Scopus (33) Google Scholar If miR-433 is increased in renal fibrosis, this miRNA might be detected in blood or urine from the diseased mice. (3) What is the best way to inhibit miR-433 in human patients? Li et al. used the ultrasound method to deliver the miR-433 KD plasmid into mouse models. Is it also useful for human patients? Some researchers use chemically modified oligonucleotides to inhibit miRNAs.2.Kato M. Natarajan R. MicroRNA circuits in transforming growth factor-beta actions and diabetic nephropathy.Semin Nephrol. 2012; 32: 253-260Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 8.Deshpande S.D. Putta S. Wang M. et al.Transforming growth factor-β induced cross talk between p53 and a microRNA in the pathogenesis of diabetic nephropathy.Diabetes. 2013; 62: 3151-3162Crossref PubMed Scopus (140) Google Scholar, 9.Kato M. Arce L. Wang M. et al.A microRNA circuit mediates transforming growth factor-beta1 autoregulation in renal glomerular mesangial cells.Kidney Int. 2011; 80: 358-368Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar Which of those methods mentioned above is a safer and more effective way? (4) Can renal fibrosis be reduced in miR-433 KO mice, as was observed in other miRNA KO mice?8.Deshpande S.D. Putta S. Wang M. et al.Transforming growth factor-β induced cross talk between p53 and a microRNA in the pathogenesis of diabetic nephropathy.Diabetes. 2013; 62: 3151-3162Crossref PubMed Scopus (140) Google Scholar (5) Might small molecules that inhibit transcription of miR-433 or downstream signaling be better targets? Some cancer drugs are suggested to be useful to suppress Smad or Akt signaling and inhibit miRNA expression and renal fibrosis.10.Kato M. Dang V. Wang M. et al.TGF-beta induces acetylation of chromatin and of Ets-1 to alleviate repression of miR-192 in diabetic nephropathy.Sci Signal. 2013; 6 ([online]): ra43Crossref PubMed Scopus (110) Google Scholar,12.Sun L. Zhang D. Liu F. et al.Low-dose paclitaxel ameliorates fibrosis in the remnant kidney model by down-regulating miR-192.J Pathol. 2011; 225: 364-377Crossref PubMed Scopus (100) Google Scholar As shown by Li et al.,5.Li R. Chung A.C.K. Dong Y. et al.The microRNA miR-433 promotes renal fibrosis by amplifying the TGF-β/Smad3-Azin1 pathway.Kidney Int. 2013; 84: 1129-1144Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar would overexpression of Azin1 or antizyme siRNA also be effective to suppress renal fibrosis? Or would a combination of these candidates be better? (6) Is miR-433 inhibition also useful for fibrosis in other organs in general? Although the world of miRNA still appears complicated in renal diseases,2.Kato M. Natarajan R. MicroRNA circuits in transforming growth factor-beta actions and diabetic nephropathy.Semin Nephrol. 2012; 32: 253-260Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 3.Chandrasekaran K. Karolina D.S. Sepramaniam S. et al.Role of microRNAs in kidney homeostasis and disease.Kidney Int. 2012; 81: 617-627Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 4.Kasinath B.S. Feliers D. The complex world of kidney microRNAs.Kidney Int. 2011; 80: 334-337Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar identifying more miRNAs related to renal fibrosis would provide more insights into diagnosis and treatment of renal fibrosis. Pathogenesis and symptoms vary from patient to patient. Because of the development of recent technologies, more precise detection of miRNAs and suitable delivery methods are expected to be established in the near future. We need definitively to treat patients with the right strategy (targeting the right miRNAs) based on the precise diagnosis (which miRNAs are right for particular patients), similar to tailor-made medicine. The author is grateful to Melody Wang for critical reading and editing of the manuscript.