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doi: 10.1111/1753-0407.12242
Journal of Diabetes 7 (2015) 462–464
C O M M E N TA R Y
Human antigen R: A novel therapeutic target for diabetic nephropathy? The prevalence of diabetes among adults has reached 6.4% worldwide and 11.6% in China.1,2 As the leading cause of end-stage renal disease (ESRD), diabetic renal complications, or diabetic nephropathy (DN), has become a very serious public health concern.3,4 DN is characterized by sequential pathophysiological events, including glomerular hypertrophy, mesangial expansion, thickening of glomerular basement membrane, podocyte loss and foot process effacement, and tubulointerstitial fibrosis due to accumulation of extracelluar matrix (ECM) proteins. Endothelial dysfunction and inflammation mediated by infiltrating macrophages are also involved in the pathogenesis of DN.5 DN is generally believed to be the result of complex interactions between metabolic and hemodynamic factors.6,7 High glucose (HG) increases the generation of advanced glycation end products (AGEs) and the levels of growth factors, especially transforming growth factor β1 (TGF-β1) and connective growth factor (CTGF), two fibrogenic factors in renal tissue.6,8 Multiple signal transduction mechanisms and kinases including oxidant stress, gluco-and lipotoxicity, protein kinase C, Akt kinase, receptor and nonreceptor protein tyrosine kinases have been implicated in the development of DN, activating key effectors, such as Smads and NF-κB, and growth factors leading to increased expression of pro-inflammatory cytokines, cell cycle genes, profibrotic and ECM genes involved in DN.6,8 The key pathological change in DN is renal fibrosis, including glomerulosclerosis and tubulointerstitial fibrosis. Increasing evidence indicates that tubular epithelialmesenchymal transition (EMT) plays a critical role in these processes. EMT manifests a phenotypical change through which epithelial cells lose their epithelial characteristics and transition into mesenchymal/myofibroblast cells.9,10 The resultant morphological changes occur with the loss of epithelial cell adhesion molecules, such as E-cadherin and cytokeratin; the appearance of the mesenchymal markers, including α-SMA and vimentin; and cytoskeletal remodeling, resulting in glomerular and tubular structural disruption.10 In these processes, many factors, in particular TGF-β1 and CTGF, trigger EMT, while repression of the transcription factors Snail and c-fos is important for the maintenance of epithelial morphology. Recently, the importance of epigenetic mechanisms in DN has attracted great attention. At the post462
transcriptional level, gene expression is regulated by two major types of transbinding factors, i.e. microRNAs (miRNAs) and RNA binding proteins (RBPs). miRNAs are a large group of small (19–23-nt-long) non-coding RNAs that can regulate gene expression at the posttranscriptional level mainly by blocking translation or promoting cleavage of their target mRNAs,11 playing roles in diverse biological processes and many diseases.12 In contrast, RBPs compose a vast group of structurally and functionally distinct proteins, which regulate mRNA stability and translation rate by interacting with target mRNAs via different RNA interaction motifs.13,14 RBPs are different from miRNAs in both structure and complexity and perform multiple functions regulating all aspects of RNA metabolism.14 Although the mechanisms are not completely the same, both miRNAs and RBPs interact with the 3′-untranslated region (UTR) of target mRNAs to modulate mRNA stability and translation. The human antigen R (HuR), which represents one of the best characterized RBPs, is an approximately 34 kD protein ubiquitously expressed and functionally involved in modulating the stability and translational efficiency of mRNAs by interacting with AU- or U-rich sequence elements (ARE) in the 3′-UTR. A large body of evidence demonstrates that HuR is involved in the regulation of various cellular processes, including cell cycle regulation, stress response, cell apoptosis, and tumor development.15,16 In addition, HuR has been strongly implicated in the inflammatory process. In various cell types, HuR binds transcripts encoding inflammatory cytokines, such as IL-6, IL-8, TNF-α, TGF-β, and IFN-γ, and pro-inflammatory mediators, including COX-2 and iNOS, thus promoting the expression of these proteins.17 HuR has also been found to be involved in the fibrotic process and ECM remodeling. In renal mesangial cells, HuR has been shown to promote matrix metallopeptidase 9 (MMP-9) expression by stabilizing MMP-9 mRNA, resulting in remodeling of the extracellular matrix.18 However, whether HuR is also involved in renal fibrosis, especially EMTinduced renal fibrosis, remains unclear. In the present study, Yu et al. have reported an additional mechanism involved in the pathogenesis of DN, in which they showed that dysfunction of the RNA binding protein HuR may promote EMT process in diabetic
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Commentary
Figure 1 Schematic overview of human antigen R (HuR)-mediated posttranscriptional regulation of high glucose-induced epithelial-mesenchymal transition (EMT) in renal tubular epithelial cells. High glucose induced-EMT through HuR-mediated posttranscriptional regulation of transforming growth factor-β1 (TGF-β1), connective growth factor (CTGF), Snail, and c-fos transcripts. Suppression of HuR may block high glucose-induced tubular EMT and renal fibrosis in diabetic kidney.
kidneys.19 They found that cytoplasmic HuR expression was elevated in the kidneys of diabetic patients and rats in addition to characteristic EMT changes. High glucose treatment also increased cytoplasmic HuR expression and EMT in human proximal tubular epithelial cells (HK-2 cells). Silencing of HuR significantly blocked EMT in high glucose-stimulated HK2 cells via increasing E-cadherin expression and reducing α-SMA and vimentin expression. Furthermore, HuR was found to bind to the 3′-UTR of critical cytokines (CTGF and TGF-β1) and transcription factors (c-fos and Snail) involved in the EMT process, and the silencing of HuR markedly reduced the expression levels of these proteins19 (Fig. 1). These findings suggest HuR might represent a novel potential target for preventing high glucose-induced EMT in renal proximal tubular epithelial cells, eventually blocking the process of renal fibrosis. Although the present study did not provide further evidence supporting the efficacy of in vivo suppression of HuR in attenuating DN in animal models, it may shed light on the underlying molecular and cellular mechanisms mediating the pathogenesis of diabetic renal complications.
Acknowledgements This work was supported by the Ministry of Science and Technology (2012CB517504) and National Natural Science Foundation of China (81030003/81270275/ 81100611/81200511/81390351).
Disclosure None declared. Yunfeng Zhou, Xiaoyan Zhang and Youfei Guan Shenzhen University Diabetes Center, AstraZeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Health Science Center, Shenzhen, China Email: [email protected]
References 1. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010; 87: 4–14. 2. Xu Y, Wang L, He J et al. Prevalence and control of diabetes in Chinese adults. JAMA. 2013; 310: 948–59. 3. Zheng F, Guan Y. Thiazolidinediones: A novel class of drugs for the prevention of diabetic nephropathy? Kidney Int. 2007; 72: 1301–3. 4. Yang J, Zhou Y, Guan Y. PPARgamma as a therapeutic target in diabetic nephropathy and other renal diseases. Curr Opin Nephrol Hypertens. 2012; 21: 97–105. 5. Wang Y, Harris DC. Macrophages in renal disease. J Am Soc Nephrol. 2011; 22: 21–7. 6. Reddy MA, Tak Park J, Natarajan R. Epigenetic modifications in the pathogenesis of diabetic nephropathy. Semin Nephrol. 2013; 33: 341–53. 7. Kanwar YS, Sun L, Xie P et al. A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol. 2011; 6: 395–423.
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
463
Commentary
8. Sanchez AP, Sharma K. Transcription factors in the pathogenesis of diabetic nephropathy. Expert Rev Mol Med. 2009; 11: e13. 9. Carew RM, Wang B, Kantharidis P. The role of EMT in renal fibrosis. Cell Tissue Res. 2012; 347: 103–16. 10. Hills CE, Squires PE. TGF-beta1-induced epithelial-tomesenchymal transition and therapeutic intervention in diabetic nephropathy. Am J Nephrol. 2010; 31: 68–74. 11. Lim LP, Lau NC, Garrett-Engele P et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005; 433: 769–73. 12. Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem. 2010; 79: 351–79. 13. Glisovic T, Bachorik JL, Yong J et al. RNA-binding proteins and post-transcriptional gene regulation. FEBS Lett. 2008; 582: 1977–86. 14. Lunde BM, Moore C, Varani G. RNA-binding proteins: Modular design for efficient function. Nat Rev Mol Cell Biol. 2007; 8: 479–90.
464
15. Doller A, Pfeilschifter J, Eberhardt W. Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR. Cell Signal. 2008; 20: 2165–73. 16. Xiao L, Wang JY. RNA-binding proteins and microRNAs in gastrointestinal epithelial homeostasis and diseases. Curr Opin Pharmacol. 2014; 19C: 46–53. 17. Pullmann R Jr, Rabb H. HuR and other turnover- and translation-regulatory RNA-binding proteins: Implications for the kidney. Am J Physiol Renal Physiol. 2014; 306: F569–76. 18. Huwiler A, Akool elS, Aschrafi A et al. ATP potentiates interleukin-1 beta-induced MMP-9 expression in mesangial cells via recruitment of the ELAV protein HuR. J Biol Chem. 2003; 278: 51758–69. 19. Yu C, Xin W, Zhen J et al. HuR Mediated posttranscriptional regulation of epithelial-mesenchymal transition related genes in diabetic nephropathy. J Diabetes. 2014; 2014. Sep 30.
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
doi: 10.1111/1753-0407.12242
Journal of Diabetes 7 (2015) 462–464
C O M M E N TA R Y
Human antigen R: A novel therapeutic target for diabetic nephropathy? The prevalence of diabetes among adults has reached 6.4% worldwide and 11.6% in China.1,2 As the leading cause of end-stage renal disease (ESRD), diabetic renal complications, or diabetic nephropathy (DN), has become a very serious public health concern.3,4 DN is characterized by sequential pathophysiological events, including glomerular hypertrophy, mesangial expansion, thickening of glomerular basement membrane, podocyte loss and foot process effacement, and tubulointerstitial fibrosis due to accumulation of extracelluar matrix (ECM) proteins. Endothelial dysfunction and inflammation mediated by infiltrating macrophages are also involved in the pathogenesis of DN.5 DN is generally believed to be the result of complex interactions between metabolic and hemodynamic factors.6,7 High glucose (HG) increases the generation of advanced glycation end products (AGEs) and the levels of growth factors, especially transforming growth factor β1 (TGF-β1) and connective growth factor (CTGF), two fibrogenic factors in renal tissue.6,8 Multiple signal transduction mechanisms and kinases including oxidant stress, gluco-and lipotoxicity, protein kinase C, Akt kinase, receptor and nonreceptor protein tyrosine kinases have been implicated in the development of DN, activating key effectors, such as Smads and NF-κB, and growth factors leading to increased expression of pro-inflammatory cytokines, cell cycle genes, profibrotic and ECM genes involved in DN.6,8 The key pathological change in DN is renal fibrosis, including glomerulosclerosis and tubulointerstitial fibrosis. Increasing evidence indicates that tubular epithelialmesenchymal transition (EMT) plays a critical role in these processes. EMT manifests a phenotypical change through which epithelial cells lose their epithelial characteristics and transition into mesenchymal/myofibroblast cells.9,10 The resultant morphological changes occur with the loss of epithelial cell adhesion molecules, such as E-cadherin and cytokeratin; the appearance of the mesenchymal markers, including α-SMA and vimentin; and cytoskeletal remodeling, resulting in glomerular and tubular structural disruption.10 In these processes, many factors, in particular TGF-β1 and CTGF, trigger EMT, while repression of the transcription factors Snail and c-fos is important for the maintenance of epithelial morphology. Recently, the importance of epigenetic mechanisms in DN has attracted great attention. At the post462
transcriptional level, gene expression is regulated by two major types of transbinding factors, i.e. microRNAs (miRNAs) and RNA binding proteins (RBPs). miRNAs are a large group of small (19–23-nt-long) non-coding RNAs that can regulate gene expression at the posttranscriptional level mainly by blocking translation or promoting cleavage of their target mRNAs,11 playing roles in diverse biological processes and many diseases.12 In contrast, RBPs compose a vast group of structurally and functionally distinct proteins, which regulate mRNA stability and translation rate by interacting with target mRNAs via different RNA interaction motifs.13,14 RBPs are different from miRNAs in both structure and complexity and perform multiple functions regulating all aspects of RNA metabolism.14 Although the mechanisms are not completely the same, both miRNAs and RBPs interact with the 3′-untranslated region (UTR) of target mRNAs to modulate mRNA stability and translation. The human antigen R (HuR), which represents one of the best characterized RBPs, is an approximately 34 kD protein ubiquitously expressed and functionally involved in modulating the stability and translational efficiency of mRNAs by interacting with AU- or U-rich sequence elements (ARE) in the 3′-UTR. A large body of evidence demonstrates that HuR is involved in the regulation of various cellular processes, including cell cycle regulation, stress response, cell apoptosis, and tumor development.15,16 In addition, HuR has been strongly implicated in the inflammatory process. In various cell types, HuR binds transcripts encoding inflammatory cytokines, such as IL-6, IL-8, TNF-α, TGF-β, and IFN-γ, and pro-inflammatory mediators, including COX-2 and iNOS, thus promoting the expression of these proteins.17 HuR has also been found to be involved in the fibrotic process and ECM remodeling. In renal mesangial cells, HuR has been shown to promote matrix metallopeptidase 9 (MMP-9) expression by stabilizing MMP-9 mRNA, resulting in remodeling of the extracellular matrix.18 However, whether HuR is also involved in renal fibrosis, especially EMTinduced renal fibrosis, remains unclear. In the present study, Yu et al. have reported an additional mechanism involved in the pathogenesis of DN, in which they showed that dysfunction of the RNA binding protein HuR may promote EMT process in diabetic
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Commentary
Figure 1 Schematic overview of human antigen R (HuR)-mediated posttranscriptional regulation of high glucose-induced epithelial-mesenchymal transition (EMT) in renal tubular epithelial cells. High glucose induced-EMT through HuR-mediated posttranscriptional regulation of transforming growth factor-β1 (TGF-β1), connective growth factor (CTGF), Snail, and c-fos transcripts. Suppression of HuR may block high glucose-induced tubular EMT and renal fibrosis in diabetic kidney.
kidneys.19 They found that cytoplasmic HuR expression was elevated in the kidneys of diabetic patients and rats in addition to characteristic EMT changes. High glucose treatment also increased cytoplasmic HuR expression and EMT in human proximal tubular epithelial cells (HK-2 cells). Silencing of HuR significantly blocked EMT in high glucose-stimulated HK2 cells via increasing E-cadherin expression and reducing α-SMA and vimentin expression. Furthermore, HuR was found to bind to the 3′-UTR of critical cytokines (CTGF and TGF-β1) and transcription factors (c-fos and Snail) involved in the EMT process, and the silencing of HuR markedly reduced the expression levels of these proteins19 (Fig. 1). These findings suggest HuR might represent a novel potential target for preventing high glucose-induced EMT in renal proximal tubular epithelial cells, eventually blocking the process of renal fibrosis. Although the present study did not provide further evidence supporting the efficacy of in vivo suppression of HuR in attenuating DN in animal models, it may shed light on the underlying molecular and cellular mechanisms mediating the pathogenesis of diabetic renal complications.
Acknowledgements This work was supported by the Ministry of Science and Technology (2012CB517504) and National Natural Science Foundation of China (81030003/81270275/ 81100611/81200511/81390351).
Disclosure None declared. Yunfeng Zhou, Xiaoyan Zhang and Youfei Guan Shenzhen University Diabetes Center, AstraZeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Health Science Center, Shenzhen, China Email: [email protected]
References 1. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010; 87: 4–14. 2. Xu Y, Wang L, He J et al. Prevalence and control of diabetes in Chinese adults. JAMA. 2013; 310: 948–59. 3. Zheng F, Guan Y. Thiazolidinediones: A novel class of drugs for the prevention of diabetic nephropathy? Kidney Int. 2007; 72: 1301–3. 4. Yang J, Zhou Y, Guan Y. PPARgamma as a therapeutic target in diabetic nephropathy and other renal diseases. Curr Opin Nephrol Hypertens. 2012; 21: 97–105. 5. Wang Y, Harris DC. Macrophages in renal disease. J Am Soc Nephrol. 2011; 22: 21–7. 6. Reddy MA, Tak Park J, Natarajan R. Epigenetic modifications in the pathogenesis of diabetic nephropathy. Semin Nephrol. 2013; 33: 341–53. 7. Kanwar YS, Sun L, Xie P et al. A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol. 2011; 6: 395–423.
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
463
Commentary
8. Sanchez AP, Sharma K. Transcription factors in the pathogenesis of diabetic nephropathy. Expert Rev Mol Med. 2009; 11: e13. 9. Carew RM, Wang B, Kantharidis P. The role of EMT in renal fibrosis. Cell Tissue Res. 2012; 347: 103–16. 10. Hills CE, Squires PE. TGF-beta1-induced epithelial-tomesenchymal transition and therapeutic intervention in diabetic nephropathy. Am J Nephrol. 2010; 31: 68–74. 11. Lim LP, Lau NC, Garrett-Engele P et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005; 433: 769–73. 12. Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem. 2010; 79: 351–79. 13. Glisovic T, Bachorik JL, Yong J et al. RNA-binding proteins and post-transcriptional gene regulation. FEBS Lett. 2008; 582: 1977–86. 14. Lunde BM, Moore C, Varani G. RNA-binding proteins: Modular design for efficient function. Nat Rev Mol Cell Biol. 2007; 8: 479–90.
464
15. Doller A, Pfeilschifter J, Eberhardt W. Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR. Cell Signal. 2008; 20: 2165–73. 16. Xiao L, Wang JY. RNA-binding proteins and microRNAs in gastrointestinal epithelial homeostasis and diseases. Curr Opin Pharmacol. 2014; 19C: 46–53. 17. Pullmann R Jr, Rabb H. HuR and other turnover- and translation-regulatory RNA-binding proteins: Implications for the kidney. Am J Physiol Renal Physiol. 2014; 306: F569–76. 18. Huwiler A, Akool elS, Aschrafi A et al. ATP potentiates interleukin-1 beta-induced MMP-9 expression in mesangial cells via recruitment of the ELAV protein HuR. J Biol Chem. 2003; 278: 51758–69. 19. Yu C, Xin W, Zhen J et al. HuR Mediated posttranscriptional regulation of epithelial-mesenchymal transition related genes in diabetic nephropathy. J Diabetes. 2014; 2014. Sep 30.
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
