Chronic inflammation is a major contributor to obesity-related renal damage. Recent studies have demonstrated that microRNA (miR)-155 is closely associated with hyperglycemia-induced nephropathy, but whether renal miR-155 participates in the inflammatory response and development of obesity-related nephropathy is unknown. In present study, we investigated the pathophysiological role of renal miR-155 in palmitic acid (PA)-treated endothelial cell and high-fat-diet (HFD)-fed mouse models by specific miR-155 sponge. Mice fed with HFD exhibited higher levels of renal miR-155, which positively correlated with urine microalbumin and blood urea nitrogen. In vitro study, mouse renal vascular endothelial cells stimulated with PA also showed higher miR-155 levels, accompanied with increased inflammatory response. Suppression of renal miR-155 effectively attenuated HFD-induced renal structural damages and dysfunction. MiR-155 sponge treatment also significantly decreased NF-κB signaling and downstream gene expression in vitro and in vivo. The obesity-increased macrophage infiltration and lipotoxicity was decreased in mouse kidney after miR-155 sponge treatment. Mechanistically, miR-155 directly targeted 3′-UTR of SHIP1/INPP5D and suppressed its expression in vitro and in vivo, whereas silence of SHIP1/INPP5D abolished the renal protective benefits of miR-155 sponge in obese mice. Taken together, present findings for the first time provided evidence for the potential role of miR-155 in obesity-related nephropathy and clarified that SHIP1/NF-κB signaling was a potential molecular mechanism.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Grundy, S.M. 2004. Obesity, metabolic syndrome, and cardiovascular disease. The Journal of Clinical Endocrinology and Metabolism 89: 2595–2600.
Seidell, J.C. 2000. Obesity, insulin resistance and diabetes--a worldwide epidemic. The British Journal of Nutrition 83 (Suppl 1): S5–S8.
Maric, C., and J.E. Hall. 2011. Obesity, metabolic syndrome and diabetic nephropathy. Contributions to Nephrology 170: 28–35.
Bayliss, G., L.A. Weinrauch, and J.A. D'Elia. 2012. Pathophysiology of obesity-related renal dysfunction contributes to diabetic nephropathy. Current Diabetes Reports 12: 440–446.
Elmarakby, A.A., and J.C. Sullivan. 2012. Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovascular Therapeutics 30: 49–59.
Wada, J., and H. Makino. 2013. Inflammation and the pathogenesis of diabetic nephropathy. Clinical Science 124: 139–152.
Lim, A.K., and G.H. Tesch. 2012. Inflammation in diabetic nephropathy. Mediators of Inflammation 2012: 146154.
Lennon, R., D. Pons, M.A. Sabin, C. Wei, J.P. Shield, R.J. Coward, J.M. Tavare, P.W. Mathieson, M.A. Saleem, and G.I. Welsh. 2009. Saturated fatty acids induce insulin resistance in human podocytes: Implications for diabetic nephropathy. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 24: 3288–3296.
de Vries, A.P., P. Ruggenenti, X.Z. Ruan, M. Praga, J.M. Cruzado, I.M. Bajema, V.D. D'Agati, H.J. Lamb, D. Pongrac Barlovic, R. Hojs, M. Abbate, R. Rodriquez, C.E. Mogensen, E. Porrini, and ERA-EDTA Working Group Diabesity. 2014. Fatty kidney: Emerging role of ectopic lipid in obesity-related renal disease. The lancet Diabetes & endocrinology 2: 417–426.
Zhang, M.Z., Y. Wang, P. Paueksakon, and R.C. Harris. 2014. Epidermal growth factor receptor inhibition slows progression of diabetic nephropathy in association with a decrease in endoplasmic reticulum stress and an increase in autophagy. Diabetes 63: 2063–2072.
Liu, G., Y. Sun, Z. Li, T. Song, H. Wang, Y. Zhang, and Z. Ge. 2008. Apoptosis induced by endoplasmic reticulum stress involved in diabetic kidney disease. Biochemical and Biophysical Research Communications 370: 651–656.
Lu, Y.C., W.C. Yeh, and P.S. Ohashi. 2008. LPS/TLR4 signal transduction pathway. Cytokine 42: 145–151.
Conner, E.M., and M.B. Grisham. 1996. Inflammation, free radicals, and antioxidants. Nutrition 12: 274–277.
Fernandez-Sanchez, A., E. Madrigal-Santillan, M. Bautista, J. Esquivel-Soto, A. Morales-Gonzalez, C. Esquivel-Chirino, et al. 2011. Inflammation, oxidative stress, and obesity. International Journal of Molecular Sciences 12: 3117–3132.
Utimura, R., C.K. Fujihara, A.L. Mattar, D.M. Malheiros, I.L. Noronha, and R. Zatz. 2003. Mycophenolate mofetil prevents the development of glomerular injury in experimental diabetes. Kidney International 63: 209–216.
Zhang, Y., B. Chen, X.H. Hou, G.J. Guan, G. Liu, H.Y. Liu, et al. 2007. Effects of mycophenolate mofetil, valsartan and their combined therapy on preventing podocyte loss in early stage of diabetic nephropathy in rats. Chinese Medical Journal 120: 988–995.
Rodriguez-Iturbe, B., Y. Quiroz, A. Shahkarami, Z. Li, and N.D. Vaziri. 2005. Mycophenolate mofetil ameliorates nephropathy in the obese Zucker rat. Kidney International 68: 1041–1047.
An, H., H. Xu, M. Zhang, J. Zhou, T. Feng, C. Qian, et al. 2005. Src homology 2 domain-containing inositol-5-phosphatase 1 (SHIP1) negatively regulates TLR4-mediated LPS response primarily through a phosphatase activity- and PI-3K-independent mechanism. Blood 105: 4685–4692.
Conde, C., X. Rambout, M. Lebrun, A. Lecat, E. Di Valentin, F. Dequiedt, et al. 2012. The inositol phosphatase SHIP-1 inhibits NOD2-induced NF-kappaB activation by disturbing the interaction of XIAP with RIP2. PLoS One 7: e41005.
Lau, N.C., L.P. Lim, E.G. Weinstein, and D.P. Bartel. 2001. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294: 858–862.
Zhang, Z., H. Peng, J. Chen, X. Chen, F. Han, X. Xu, X. He, and N. Yan. 2009. MicroRNA-21 protects from mesangial cell proliferation induced by diabetic nephropathy in db/db mice. FEBS Letters 583: 2009–2014.
Putta, S., L. Lanting, G. Sun, G. Lawson, M. Kato, and R. Natarajan. 2012. Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy. Journal of the American Society of Nephrology : JASN 23: 458–469.
Wang, Q., Y. Wang, A.W. Minto, J. Wang, Q. Shi, X. Li, and R.J. Quigg. 2008. MicroRNA-377 is up-regulated and can lead to increased fibronectin production in diabetic nephropathy. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology 22: 4126–4135.
Lin, X., Y. You, J. Wang, Y. Qin, P. Huang, and F. Yang. 2015. MicroRNA-155 deficiency promotes nephrin acetylation and attenuates renal damage in hyperglycemia-induced nephropathy. Inflammation 38: 546–554.
Wang, G., B.C. Kwan, F.M. Lai, K.M. Chow, P.K. Li, and C.C. Szeto. 2011. Elevated levels of miR-146a and miR-155 in kidney biopsy and urine from patients with IgA nephropathy. Disease Markers 30: 171–179.
Wang, H., W. Peng, X. Shen, Y. Huang, X. Ouyang, and Y. Dai. 2012. Circulating levels of inflammation-associated miR-155 and endothelial-enriched miR-126 in patients with end-stage renal disease. Brazilian journal of medical and biological research =. Revista brasileira de pesquisas medicas e biologicas 45: 1308–1314.
Baeuerle, P.A., and V.R. Baichwal. 1997. NF-kappa B as a frequent target for immunosuppressive and anti-inflammatory molecules. Advances in Immunology 65: 111–137.
Nguyen, D., F. Ping, W. Mu, P. Hill, R.C. Atkins, and S.J. Chadban. 2006. Macrophage accumulation in human progressive diabetic nephropathy. Nephrology 11: 226–231.
O'Connell, R.M., A.A. Chaudhuri, D.S. Rao, and D. Baltimore. 2009. Inositol phosphatase SHIP1 is a primary target of miR-155. Proceedings of the National Academy of Sciences of the United States of America 106: 7113–7118.
Kurowska-Stolarska, M., S. Alivernini, L.E. Ballantine, D.L. Asquith, N.L. Millar, D.S. Gilchrist, J. Reilly, M. Ierna, A.R. Fraser, B. Stolarski, C. McSharry, A.J. Hueber, D. Baxter, J. Hunter, S. Gay, F.Y. Liew, and I.B. McInnes. 2011. MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proceedings of the National Academy of Sciences of the United States of America 108: 11193–11198.
Jin, H.M., T.J. Kim, J.H. Choi, M.J. Kim, Y.N. Cho, K.I. Nam, S.J. Kee, J. Moon, S.Y. Choi, D.J. Park, S.S. Lee, and Y.W. Park. 2014. MicroRNA-155 as a proinflammatory regulator via SHIP-1 down-regulation in acute gouty arthritis. Arthritis Research & Therapy 16: R88.
Awad, A.S., H. You, T. Gao, T.K. Cooper, S.A. Nedospasov, J. Vacher, P.F. Wilkinson, F.X. Farrell, and W. Brian Reeves. 2015. Macrophage-derived tumor necrosis factor-alpha mediates diabetic renal injury. Kidney International 88: 722–733.
Klessens, C.Q.F., M. Zandbergen, R. Wolterbeek, J.A. Bruijn, T.J. Rabelink, I.M. Bajema, et al. 2017. Macrophages in diabetic nephropathy in patients with type 2 diabetes. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 32: 1322–1329.
O'Connell, R.M., K.D. Taganov, M.P. Boldin, G. Cheng, and D. Baltimore. 2007. MicroRNA-155 is induced during the macrophage inflammatory response. Proceedings of the National Academy of Sciences of the United States of America 104: 1604–1609.
Vyas, P., and D. Vohora. 2017. Phosphoinositide-3-kinases as the novel therapeutic targets for the inflammatory diseases: Current and future perspectives. Current Drug Targets 18: 1622–1640.
This work was supported by Wenzhou Committee of Science and Technology of China (ZS2017008, Y20170055 and Y20180159), the Zhejiang Medical Science and Technology Research Fund Project of China (LY14H050006), the Guangdong Medical Science and Technology Research Fund Project of China (A2018042), the Guangzhou Science and Technology Project of China (20170420167), and Zhejiang Province Natural Science Foundation (LY16H150007).
Conflict of Interest
The authors declare that they have no conflicts of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Zheng, C., Zhang, J., Chen, X. et al. MicroRNA-155 Mediates Obesity-Induced Renal Inflammation and Dysfunction. Inflammation 42, 994–1003 (2019). https://doi.org/10.1007/s10753-019-00961-y