L-Lysine Ameliorates Diabetic Nephropathy in Rats with Streptozotocin-Induced Diabetes Mellitus

Faezeh Jozi, Nejat Kheiripour, Maryam Akhavan Taheri, Abolfazl Ardjmand, Gholamreza Ghavipanjeh, Zahra Nasehi, Mohammad Esmaeil Shahaboddin, Faezeh Jozi, Nejat Kheiripour, Maryam Akhavan Taheri, Abolfazl Ardjmand, Gholamreza Ghavipanjeh, Zahra Nasehi, Mohammad Esmaeil Shahaboddin

Abstract

Introduction: Diabetic nephropathy is one of the leading causes of end-stage renal disease worldwide. Uncontrolled hyperglycemia and subsequent production of glycation end-products activate the paths which lead to diabetic nephropathy. The aim of this study was to assess the effects of L-lysine on antioxidant capacity, biochemical factors, kidney function, HSP70 level, and the expression of the TGFβ, VEGF, and RAGE genes in rats with streptozocin-induced diabetes mellitus.

Methods: Thirty-two male Wistar rats were randomly allocated to four eight-rat groups, namely, a healthy group, a diabetic group treated with vehicle (DM + vehicle), a diabetic group treated with L-lysine (DM + Lys), and a healthy group treated with L-lysine (healthy + Lys). Rats in the DM + Lys and the healthy + Lys groups were treated with L-lysine 0.15%. The levels of fasting blood glucose, insulin, HbA1C, advanced glycation end-products (AGEs), lipid profile, serum creatinine, blood urea nitrogen, glomerular filtration rate, urine microalbumin, oxidative stress parameters, kidney histology and morphology, and TGFβ, VEGF, and RAGE gene expressions were assessed. Findings. An eight-week treatment with L-lysine significantly reduced the levels of fasting blood glucose, AGEs, kidney function parameters, oxidative stress parameters, lipid profile, and the TGFβ, VEGF, and RAGE gene expression and significantly increased the levels of serum insulin and tissue HSP70.

Conclusion: Treatment with L-lysine seems to slow down the progression of diabetic nephropathy.

Conflict of interest statement

The authors declare no conflict of interests.

Copyright © 2022 Faezeh Jozi et al.

Figures

Figure 1
Figure 1
Level of fasting blood glucose in different groups (A#: significant difference between the healthy group and other groups; B#: significant difference between the DM + Vehicle group and other groups).
Figure 2
Figure 2
The expression of the RAGE (a), TGF (b), and VEGF (c) genes in kidney tissue (#: significant difference between the DM + Vehicle group and other groups).
Figure 3
Figure 3
Histological morphology of kidney tissue in the healthy group (a), healthy + Lys group (b), DM + vehicle group (c and d), and DM + Lys group (e and f) (magnification: ×400).

References

    1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care . 2009;32(Supplement_1):S62–S67. doi: 10.2337/dc09-S062.
    1. Shahab U., Faisal M., Alatar A. A., Ahmad S. Impact of wedelolactone in the anti-glycation and anti-diabetic activity in experimental diabetic animals. IUBMB Life . 2018;70(6):547–552. doi: 10.1002/iub.1744.
    1. Fishman S. L., Sonmez H., Basman C., Singh V., Poretsky L. The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review. Molecular Medicine . 2018;24(1):p. 59. doi: 10.1186/s10020-018-0060-3.
    1. Siddiqui Z., Faisal M., Alatar A. A., Ahmad S. Glycation of hemoglobin leads to the immunogenicity as a result of neo-epitope generation. International Journal of Biological Macromolecules . 2019;123:427–435. doi: 10.1016/j.ijbiomac.2018.11.063.
    1. Pathomthongtaweechai N., Chutipongtanate S. AGE/RAGE signaling-mediated endoplasmic reticulum stress and future prospects in non-coding RNA therapeutics for diabetic nephropathy. Biomedicine & Pharmacotherapy . 2020;131, article 110655 doi: 10.1016/j.biopha.2020.110655.
    1. Fanelli C., Noreddin A., Nunes A. Chronic Kidney Disease: From Pathophysiology to Clinical Improvements . IntechOpen London; 2018. Inflammation in Nonimmune-Mediated Chronic Kidney.
    1. Serban A. I., Stanca L., Geicu O. I., Munteanu M. C., Dinischiotu A. RAGE and TGF-β1 cross-talk regulate extracellular matrix turnover and cytokine synthesis in AGEs exposed fibroblast cells. PLoS One . 2016;11(3, article e0152376) doi: 10.1371/journal.pone.0152376.
    1. Steenbeke M., Speeckaert R., Desmedt S., Glorieux G., Delanghe J. R., Speeckaert M. M. The role of advanced glycation end products and its soluble receptor in kidney diseases. International Journal of Molecular Sciences . 2022;23(7):p. 3439. doi: 10.3390/ijms23073439.
    1. Kottaisamy C. P. D., Raj D. S., Prasanth Kumar V., Sankaran U. Experimental animal models for diabetes and its related complications—a review. Laboratory Animal Research . 2021;37(1):p. 23. doi: 10.1186/s42826-021-00101-4.
    1. Roskoski R. Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas. Pharmacological Research . 2017;120:116–132. doi: 10.1016/j.phrs.2017.03.010.
    1. Wang X., Bove A. M., Simone G., Ma B. Molecular bases of VEGFR-2-mediated physiological function and pathological role. Frontiers in Cell and Development Biology . 2020;8, article 599281 doi: 10.3389/fcell.2020.599281.
    1. Karaman S., Leppänen V. M., Alitalo K. Vascular endothelial growth factor signaling in development and disease. Development . 2018;145(14) doi: 10.1242/dev.151019.
    1. Khan M. Y., Alouffi S., Khan M. S., Husain F. M., Akhter F., Ahmad S. The neoepitopes on methylglyoxal (MG) glycated LDL create autoimmune response; autoimmunity detection in T2DM patients with varying disease duration. Cellular Immunology . 2020;351, article 104062 doi: 10.1016/j.cellimm.2020.104062.
    1. Li Y., Khan M. S., Akhter F., Husain F. M., Ahmad S., Chen L. The non-enzymatic glycation of LDL proteins results in biochemical alterations - a correlation study of Apo B100-AGE with obesity and rheumatoid arthritis. International Journal of Biological Macromolecules . 2019;122:195–200. doi: 10.1016/j.ijbiomac.2018.09.107.
    1. Levy-Sakin M., Berger O., Feibish N., et al. The influence of chemical chaperones on enzymatic activity under thermal and chemical stresses: common features and variation among diverse chemical families. PLoS One . 2014;9(2, article e88541) doi: 10.1371/journal.pone.0088541.
    1. Jafarnejad A., Bathaie S. Z., Nakhjavani M., Hassan M. Z., Banasadegh S. The improvement effect of L-Lys as a chemical chaperone on STZ-induced diabetic rats, protein structure and function. Diabetes/Metabolism Research and Reviews . 2008;24(1):64–73. doi: 10.1002/dmrr.769.
    1. Radons J. The human HSP70 family of chaperones: where do we stand? Cell Stress & Chaperones . 2016;21(3):379–404. doi: 10.1007/s12192-016-0676-6.
    1. Stetler R. A., Gan Y., Zhang W., et al. Heat shock proteins: cellular and molecular mechanisms in the central nervous system. Progress in Neurobiology . 2010;92(2):184–211. doi: 10.1016/j.pneurobio.2010.05.002.
    1. Bahmani F., Bathaie S. Z., Aldavood S. J., Ghahghaei A. Prevention of α-crystallin glycation and aggregation using l-lysine results in the inhibition of in vitro catalase heat-induced-aggregation and suppression of cataract formation in the diabetic rat. International Journal of Biological Macromolecules . 2019;132:1200–1207. doi: 10.1016/j.ijbiomac.2019.04.037.
    1. Sulochana K. N., Punitham R., Ramakrishnan S. Beneficial effect of lysine and amino acids on cataractogenesis in experimental diabetes through possible antiglycation of lens proteins. Experimental Eye Research . 1998;67(5):597–601. doi: 10.1006/exer.1998.0547.
    1. Natarajan Sulochana K., Lakshmi S., Punitham R., Arokiasamy T., Sukumar B., Ramakrishnan S. Effect of oral supplementation of free amino acids in type 2 diabetic patients-- a pilot clinical trial. Medical Science Monitor . 2002;8(3):CR131–CR137.
    1. Han H., Yin J., Wang B., et al. Effects of dietary lysine restriction on inflammatory responses in piglets. Scientific Reports . 2018;8(1):p. 2451. doi: 10.1038/s41598-018-20689-3.
    1. Li P., Yin Y. L., Li D., Woo Kim S., Wu G. Amino acids and immune function. The British Journal of Nutrition . 2007;98(2):237–252. doi: 10.1017/S000711450769936X.
    1. Chen C., Sander J. E., Dale N. M. The effect of dietary lysine deficiency on the immune response to Newcastle disease vaccination in chickens. Avian Diseases . 2003;47(4):1346–1351. doi: 10.1637/7008.
    1. Cheng J., Tang J. C., Pan M. X., et al. l-Lysine confers neuroprotection by suppressing inflammatory response via microRNA-575/PTEN signaling after mouse intracerebral hemorrhage injury. Experimental Neurology . 2020;327, article 113214 doi: 10.1016/j.expneurol.2020.113214.
    1. Furman B. L. Streptozotocin-induced diabetic models in mice and rats. Current Protocols . 2021;1(4, article e78) doi: 10.1002/cpz1.78.
    1. Karim P., Mohammad E. S., Mitra M., Seyyed M. M., Ali M. F., Fariba S. Glycemic index of Iranian rice. Scientific Research and Essays . 2011;6(25):5302–5307.
    1. Dansethakul P., Thapanathamchai L., Saichanma S., Worachartcheewan A., Pidetcha P. Determining a new formula for calculating low-density lipoprotein cholesterol: data mining approach. EXCLI Journal . 2015;14:478–483. doi: 10.17179/excli2015-162.
    1. Pohanka M. Glycated hemoglobin and methods for its point of care testing. Biosensors . 2021;11(3):p. 70. doi: 10.3390/bios11030070.
    1. Ammanath G., Delachi C. G., Karabacak S., et al. Colorimetric and fluorometric profiling of advanced glycation end products. ACS Applied Materials & Interfaces . 2022;14(1):94–103. doi: 10.1021/acsami.1c16261.
    1. Asemi Z., Jazayeri S., Najafi M., et al. Association between markers of systemic inflammation, oxidative stress, lipid profiles, and insulin resistance in pregnant women. ARYA Atherosclerosis . 2013;9(3):172–178.
    1. Colombo G., Clerici M., Garavaglia M. E., et al. A step-by-step protocol for assaying protein carbonylation in biological samples. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences . 2016;1019:178–190. doi: 10.1016/j.jchromb.2015.11.052.
    1. Hadwan M. H., Abed H. N. Data supporting the spectrophotometric method for the estimation of catalase activity. Data in Brief . 2016;6:194–199. doi: 10.1016/j.dib.2015.12.012.
    1. Ardjmand A., Shahaboddin M. E., Mazoochi T., Heydari A., Ghavipanjeh G. Cardioprotective effects of cerebrolysin on the lesion severity and inflammatory factors in a rat model of isoproterenol-induced myocardial injury. Pharmacological Reports . 2019;71(4):682–687. doi: 10.1016/j.pharep.2019.03.003.
    1. Gannon M. C., Nuttall F. Q. Amino acid ingestion and glucose metabolism—a review. IUBMB Life . 2010;62(9):660–668. doi: 10.1002/iub.375.
    1. Kalogeropoulou D., LaFave L., Schweim K., Gannon M. C., Nuttall F. Q. Lysine ingestion markedly attenuates the glucose response to ingested glucose without a change in insulin response. The American Journal of Clinical Nutrition . 2009;90(2):314–320. doi: 10.3945/ajcn.2008.27381.
    1. Vinson J. A., Howard T. B. Inhibition of protein glycation and advanced glycation end products by ascorbic acid and other vitamins and nutrients. The Journal of Nutritional Biochemistry . 1996;7(12):659–663. doi: 10.1016/S0955-2863(96)00128-3.
    1. Sensi M., de Rossi M. G., Celi F. S., et al. D-Lysine reduces the non-enzymatic glycation of proteins in experimental diabetes mellitus in rats. Diabetologia . 1993;36(9):797–801. doi: 10.1007/BF00400352.
    1. Yamauchi M., Sricholpech M. Lysine post-translational modifications of collagen. Essays in Biochemistry . 2012;52:113–133. doi: 10.1042/bse0520113.
    1. Sensi M., Pricci F., de Rossi M. G., Morano S., di Marlo U. D-Lysine effectively decreases the non-enzymic glycation of proteins In Vitro. Clinical Chemistry . 1989;35(3):384–387. doi: 10.1093/clinchem/35.3.384.
    1. Mirmiranpour H., Bathaie S. Z., Khaghani S., Nakhjavani M., Kebriaeezadeh A. L-Lysine supplementation improved glycemic control, decreased protein glycation, and insulin resistance in type 2 diabetic patients. International Journal of Diabetes in Developing Countries . 2021;41(4):634–643. doi: 10.1007/s13410-021-00931-x.
    1. Wang T., Crenshaw M. A., Hasan M. S., Wu G., Liao S. F. Amino Acid - New Insights and Roles in Plant and Animal . InTech; 2017. Effects of dietary lysine levels on the plasma concentrations of growth-related hormones in late-stage finishing pigs.
    1. Rorsman P., Ashcroft F. M. Pancreatic β-cell electrical activity and insulin secretion: of mice and men. Physiological Reviews . 2018;98(1):117–214. doi: 10.1152/physrev.00008.2017.
    1. Sherwani S. I., Khan H. A., Ekhzaimy A., Masood A., Sakharkar M. K. Significance of HbA1c test in diagnosis and prognosis of diabetic patients. Biomarker Insights . 2016;11:BMI.S38440–BMI.S38104. doi: 10.4137/BMI.S38440.
    1. Pei K., Gui T., Li C., et al. Recent progress on lipid intake and chronic kidney disease. BioMed Research International . 2020;2020 doi: 10.1155/2020/3680397.3680397
    1. Børsheim E., Bui Q. U. T., Tissier S., et al. Amino acid supplementation decreases plasma and liver triacylglycerols in elderly. Nutrition . 2009;25(3):281–288. doi: 10.1016/j.nut.2008.09.001.
    1. Hevia P., Visek W. Liver and serum lipids and lipoproteins of rats fed 5% L-lysine. Lipids . 1980;15(2):95–99. doi: 10.1007/BF02533883.
    1. Rabie M. H., Szilágyi M. Effects of L-carnitine supplementation of diets differing in energy levels on performance, abdominal fat content, and yield and composition of edible meat of broilers. British Journal of Nutrition . 1998;80(4):391–400. doi: 10.1017/S0007114598001457.
    1. Forbes J. M., Cooper M. E., Oldfield M. D., Thomas M. C. Role of advanced glycation end products in diabetic nephropathy. Journal of the American Society of Nephrology . 2003;14(suppl 3):S254–S258. doi: 10.1097/01.ASN.0000077413.41276.17.
    1. Tanji N., Markowitz G. S., Fu C., et al. Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. Journal of the American Society of Nephrology . 2000;11(9):1656–1666. doi: 10.1681/ASN.V1191656.
    1. Jyothirmayi G. N., Modak R., Reddi A. S. L-Lysine reduces nonenzymatic glycation of glomerular basement membrane collagen and albuminuria in diabetic rats. Nephron . 2001;87(2):148–154. doi: 10.1159/000045904.
    1. De Cosmo S., Earle K., Morocutti A., et al. Glucose-induced changes in renal haemodynamics in proteinuric type 1 (insulin-dependent) diabetic patients: inhibition by acetylsalicilic acid infusion. Diabetologia . 1993;36(7):622–627. doi: 10.1007/BF00404071.
    1. Mirmiranpour H., Bathaie S. Z., Khaghani S., Nakhjavani M., Kebriaeezadeh A. Investigation of the mechanism(s) involved in decreasing increased fibrinogen activity in hyperglycemic conditions using L-lysine supplementation. Thrombosis Research . 2012;130(3):e13–e19. doi: 10.1016/j.thromres.2012.04.010.
    1. Papadopoulou-Marketou N., Paschou S. A., Marketos N., Adamidi S., Adamidis S., Kanaka-Gantenbein C. Diabetic nephropathy in type 1 diabetes. Minerva Medica . 2018;109(3):218–228. doi: 10.23736/S0026-4806.17.05496-9.
    1. Huang D., Maulu S., Ren M., et al. Dietary lysine levels improved antioxidant capacity and immunity via the TOR and p38 MAPK signaling pathways in grass carp, Ctenopharyngodon idellus fry. Frontiers in Immunology . 2021;12 doi: 10.3389/fimmu.2021.635015.
    1. Bonnefont-Rousselot D., Bastard J. P., Jaudon M. C., Delattre J. Consequences of the diabetic status on the oxidant/antioxidant balance. Diabetes & Metabolism . 2000;26(3):163–176.
    1. Sagoo M., Gnudi L. Diabetic nephropathy: is there a role for oxidative stress? Free Radical Biology and Medicine . 2018;116:50–63. doi: 10.1016/j.freeradbiomed.2017.12.040.
    1. Shi G.-J., Shi G. R., Zhou J. Y., et al. Involvement of growth factors in diabetes mellitus and its complications: a general review. Biomedicine & Pharmacotherapy . 2018;101:510–527. doi: 10.1016/j.biopha.2018.02.105.
    1. Lu L., Peng W. H., Wang W., Wang L. J., Chen Q. J., Shen W. F. Effects of atorvastatin on progression of diabetic nephropathy and local RAGE and soluble RAGE expressions in rats. Journal of Zhejiang University. Science. B . 2011;12(8):652–659. doi: 10.1631/jzus.B1101004.
    1. Nakamura S., Li H., Adijiang A., Pischetsrieder M., Niwa T. Pyridoxal phosphate prevents progression of diabetic nephropathy. Nephrology Dialysis Transplantation . 2007;22(8):2165–2174. doi: 10.1093/ndt/gfm166.
    1. Leask A., Abraham D. J. TGF-β signaling and the fibrotic response. The FASEB Journal . 2004;18(7):816–827. doi: 10.1096/fj.03-1273rev.
    1. Zhong Z., Wheeler M. D., Li X., et al. L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent. Current Opinion in Clinical Nutrition and Metabolic Care . 2003;6(2):229–240. doi: 10.1097/00075197-200303000-00013.
    1. Hooper P. L., Hooper J. J. Loss of defense against stress: diabetes and heat shock proteins. Diabetes Technology & Therapeutics . 2005;7(1):204–208. doi: 10.1089/dia.2005.7.204.
    1. Sepponen K., Pösö A. R. The inducible form of heat shock protein 70 in the serum, colon and small intestine of the pig: comparison to conventional stress markers. Veterinary Journal . 2006;171(3):519–524. doi: 10.1016/j.tvjl.2005.01.005.
    1. Padmini E., Vijaya Geetha B. Impact of season on liver mitochondrial oxidative stress and the expression of HSP70 in grey mullets from contaminated estuary. Ecotoxicology . 2009;18(3):304–311. doi: 10.1007/s10646-008-0282-1.

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