Abstract
Zinc (Zn) is a trace element with a variety of anti-inflammatory and antioxidant effects. Zn deficiency is related to tissue fibrosis. The present study was designed to investigate the effect of Zn on renal fibrosis. Mouse models were successfully established by feeding mice diets with different concentrations of Zn. Zn deficiency induced a decrease in Zn levels in kidney tissue. The results also revealed renal vasodilation, hyperemia, and inflammatory cell infiltration, and the levels of creatinine and urea nitrogen were increased. Furthermore, the TUNEL results showed a large degree of renal cell necrosis caused by Zn deficiency. Meanwhile, the corresponding antioxidant and anti-inflammatory regulators (MT-1, MT-2, Nrf2, and TGF-β1) were detected by RT-PCR, showing that the expression of MT-1, MT-2, and Nrf2 decreased but that TGF-β1 expression increased. The results of Sirius red staining proved that the expression of collagen was increased by Zn deficiency. The immunohistochemical experiments found that the expression of α-smooth muscle actin (α-SMA) increased. ELISA showed that the expression of Collagen I, III, and IV; fibronectin (FN); and inflammatory factors (TNF-α and IL-1β) were remarkably increased. The expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12, and TIMP-1, which are extracellular matrix-regulating molecules, was detected by RT-PCR. The results showed that the expression of TIMPs was increased but that the expression of MMPs was decreased. We also obtained consistent results in vivo. All the experimental results indicated that Zn deficiency could aggravate fibrosis by increasing inflammation in the kidney.
Similar content being viewed by others
References
Lopez-Novoa JM, Martinez-Salgado C, Rodriguez-Pena AB, Lopez-Hernandez FJ (2010) Common pathophysiological mechanisms of chronic kidney disease: therapeutic perspectives. Pharmacol Ther 128:61–81
Nogueira A, Pires MJ, Oliveira PA (2017) Pathophysiological mechanisms of renal fibrosis: a review of animal models and therapeutic strategies. In vivo 31:1–22
Fogo AB (2001) Progression and potential regression of glomerulosclerosis. Kidney Int 59:804–819
Manickam N, Patel M, Griendling KK, Gorin Y, Barnes JL (2014) RhoA/Rho kinase mediates TGF-beta1-induced kidney myofibroblast activation through Poldip2/Nox4-derived reactive oxygen species. Am J Physiol Ren Physiol 307:F159–F171
Bondi CD, Manickam N, Lee DY, Block K, Gorin Y, Abboud HE, Barnes JL (2010) NAD(P)H oxidase mediates TGF-beta1-induced activation of kidney myofibroblasts. J Am Soc Nephrol : JASN 21:93–102
Cheng TH, Cheng PY, Shih NL, Chen IB, Wang DL, Chen JJ (2003) Involvement of reactive oxygen species in angiotensin II-induced endothelin-1 gene expression in rat cardiac fibroblasts. J Am Coll Cardiol 42:1845–1854
Park SA, Kim MJ, Park SY, Kim JS, Lee SJ, Woo HA, Kim DK, Nam JS, Sheen YY (2015) EW-7197 inhibits hepatic, renal, and pulmonary fibrosis by blocking TGF-beta/Smad and ROS signaling. Cell Mol Life Sci : CMLS 72:2023–2039
Kerr ME, Bender CM, Monti EJ (1996) An introduction to oxygen free radicals. Heart Lung : the journal of critical care 25:200–209 quiz 210-1
Wang S, Chi Q, Hu X, Cong Y, Li S (2019) Hydrogen sulfide-induced oxidative stress leads to excessive mitochondrial fission to activate apoptosis in broiler myocardia. Ecotoxicol Environ Saf 183:109578
Xin C, Guangliang S, Qing Z, Qingqing L, Hang Y, Yiming Z, Shu L (2020) Astilbin protects chicken peripheral blood lymphocytes from cadmium-induced necroptosis via oxidative stress and the PI3K/Akt pathway. Ecotoxicol Environ Saf 190:110064
Meng XM, Nikolic-Paterson DJ, Lan HY (2014) Inflammatory processes in renal fibrosis. Nat Rev Nephrol 10:493–503
Lan HY (2011) Diverse roles of TGF-beta/Smads in renal fibrosis and inflammation. Int J Biol Sci 7:1056–1067
Loboda A, Sobczak M, Jozkowicz A, Dulak J (2016) TGF-beta1/Smads and miR-21 in renal fibrosis and inflammation. Mediat Inflamm 2016:8319283
Liu WH, Tang NN, Zhang QD (2009) Could mycophenolate mofetil combined with benazapril delay tubulointerstitial fibrosis in 5/6 nephrectomized rats? Chin Med J 122:199–204
Kapoor C, Vaidya S, Wadhwan V, Hitesh KG, Pathak A (2016) Seesaw of matrix metalloproteinases (MMPs). J Cancer Res Ther 12:28–35
Arpino V, Brock M, Gill SE (2015) The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix biology : journal of the International Society for Matrix Biology 44-46:247–254
Wang L, Shi X, Zheng S, Xu S (2020) Selenium deficiency exacerbates LPS-induced necroptosis by regulating miR-16-5p targeting PI3K in chicken tracheal tissue. Metallomics. 12:562–571. https://doi.org/10.1039/c9mt00302a
Zhang Z, Liu Q, Yang J, Yao H, Fan R, Cao C, Liu C, Zhang S, Lei X, Xu S (2020) The proteomic profiling of multiple tissue damage in chickens for a selenium deficiency biomarker discovery. Food Funct 11(2):1312–1321
Liu J, Wang S, Zhang Q, Li X, Xu S (2020) Selenomethionine alleviates LPS-induced chicken myocardial inflammation by regulating the miR-128-3p-p38 MAPK axis and oxidative stress. Metallomics. 12(1):54–64
Rink L, Gabriel P (2000) Zinc and the immune system. Proc Nutr Soc 59:541–552
Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME (2012) Zinc and human health: an update. Arch Toxicol 86:521–534
Zinc and health: current status and future directions (2000) Proceedings of a workshop. Bethesda, Maryland, USA. November 4-5, 1998. J Nutr 130:1341S–1519S
Stefanidou M, Maravelias C, Dona A, Spiliopoulou C (2006) Zinc: a multipurpose trace element. Arch Toxicol 80:1–9
Jarosz M, Olbert M, Wyszogrodzka G, Mlyniec K, Librowski T (2017) Antioxidant and anti-inflammatory effects of zinc Zinc-dependent NF-kappaB signaling. Inflammopharmacology 25:11–24
Sun M, Zhuo W, Guo S, Liao S, Shi D, Liu J, Cheng Z, Liu Y, Niu X, Wang S, Yang D (2012) Serological survey of canine dirofilariosis in Chongqing, Kunming, Nanchang, Fuzhou, Guangzhou, Shenzhen, and Nanning in Southern China. Vet Parasitol 185(2-4):225–228
Liu J, Cheng Z, Zhou D, Zhang L, Yan Z, Wang Z, Yang D, Liu Y, Chai T (2011) Synthesis, cloning, and expression of Mycoplasma suis inorganic pyrophosphatase gene using PCR-based accurate synthesis and overlap-extension PCR, and its immunogenicity analysis. Res Vet Sci 91(3):e100–e102
Li MS, Adesina SE, Ellis CL, Gooch JL, Hoover RS, Williams CR (2017) NADPH oxidase-2 mediates zinc deficiency-induced oxidative stress and kidney damage. Am J Physiol Cell Physiol 312:C47–C55
Nalobin DS, Krasnov MS, Alipkina SI, Syrchina MS, Yamskova VP, Yamskov IA (2016) Effect of bioregulators isolated from rat liver and blood serum on the state of murine liver in roller organotypic culture after CCl4-induced fibrosis. Bull Exp Biol Med 161:604–609
Prasad AS (2014) Zinc: an antioxidant and anti-inflammatory agent: role of zinc in degenerative disorders of aging. J Trace Elem Med Biol : organ of the Society for Minerals and Trace Elements 28:364–371
Baltaci AK, Yuce K, Mogulkoc R (2018) Zinc metabolism and metallothioneins. Biol Trace Elem Res 183:22–31
Duerr GD, Dewald D, Schmitz EJ, Verfuerth L, Keppel K, Peigney C et al (2016) Metallothioneins 1 and 2 modulate inflammation and support remodeling in ischemic cardiomyopathy in mice. Mediat Inflamm 2016:7174127
Kobayashi M, Yamamoto M (2006) Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzym Regul 46:113–140
Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426
Rezaei KA, Chen Y, Cai J, Sternberg P (2008) Modulation of Nrf2-dependent antioxidant functions in the RPE by Zip2, a zinc transporter protein. Invest Ophthalmol Vis Sci 49:1665–1670
Hu HH, Chen DQ, Wang YN, Feng YL, Cao G, Vaziri ND, Zhao YY (2018) New insights into TGF-beta/Smad signaling in tissue fibrosis. Chem Biol Interact 292:76–83
Sun KH, Chang Y, Reed NI, Sheppard D (2016) α-Smooth muscle actin is an inconsistent marker of fibroblasts responsible for force-dependent TGFbeta activation or collagen production across multiple models of organ fibrosis. Am J Physiol Lung Cell Mol Physiol 310:L824–L836
Zhang X, Ritter JK, Li N (2018) Sphingosine-1-phosphate pathway in renal fibrosis. Am J Physiol Ren Physiol 315:F752–F756
Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463–516
Malemud CJ (2006) Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci : a journal and virtual library 11:1696–1701
Parks WC, Wilson CL, Lopez-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4:617–629
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Xu, R., Chen, My., Liang, W. et al. Zinc Deficiency Aggravation of ROS and Inflammatory Injury Leading to Renal Fibrosis in Mice. Biol Trace Elem Res 199, 622–632 (2021). https://doi.org/10.1007/s12011-020-02184-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12011-020-02184-x