THE EFFECT OF METFORMIN AND ITS COMBINATION WITH MODULATORS OF HYDROGEN SULPHIDE METABOLISM ON THE LEVEL OF GLYCEMIA AND THE STATE OF THE H2S SYSTEM IN THE KIDNEYS OF RATS WITH STREPTOZOTOCIN-INDUCED DIABETES
DOI:
https://doi.org/10.11603/mcch.2410-681X.2022.i4.13565Keywords:
hydrogen sulfide, glucose, metabolism, kidneys, metformin, NaHS, propargylglycine, nephrotoxicity, diabetes mellitusAbstract
Introduction. Diabetic nephropathy belongs to one of the severe microvascular complications of diabetes mellitus (DM) and is one of the causes of patient disability and mortality. An important role in the treatment of diabetic nephropathy belongs to the sugar-lowering drug metformin. The question of the molecular mechanisms of metformin’s action, in particular the role of the H2S signaling system in its pharmacological activity, remains unclear.
The aim of the study – to evaluate the effect of metformin and its combination with modulators of H2S, exchange on the level of glycemia and H2S metabolism in the kidneys of rats with streptozotocin-induced diabetes.
Materials and Methods. The experiments were performed on 75 white non-linear male rats weighing 150–240 g. The animals were divided into five groups: group 1 – control; group 2 – animals with experimental DM, which was initiated by a single intraperitoneal injection of streptozotocin (40 mg/kg of weight) in 0.1 M citrate buffer (pH 4,5); group 3 – animals with experimental DM were treated with metformin (500 mg/kg/day, intragastrically) from the 3rd to the 28th day; group 4 – animals with DM along with metformin were given NaHS (56 μmol/kg/day, intragastrically); group 5 – animals with DM along with metformin, were administered propargylglycine (PPG, 442 μmol/kg/day, intragastrically). The glucose content was determined in the peripheral blood. H2S level, activity of H2S-synthesizing enzymes (cystathionine-γ-lyase – CSE, cystathionine-β-synthase – CBS, cysteineaminotransferase/3-mercaptopyruvate sulfurtransferase – CAT/3-MST), activity of thioredoxin reductase (TRR) and rate of H2S utilization were evaluated in the supernatant of the kidney homogenate,
Results and Discussion. It was established that streptozotocin-induced diabetes (ST-diabetes) causes a significant increase in blood glucose levels (by 4.6 times, p˂0.001), a decrease of H2S contents, activity of H2S-producing enzymes (CSE, CBS and CAT / 3-MST), activity of TRR in the kidney by 33.2–58.1 % (p˂0.001) and an increase of H2S utilization rates by 79.4 % (p˂0.001) compared with control group. The use of metformin in ST-diabetes reveals hypoglycemic activity (glucose level decreases by 25.2 %, p˂0,001, compared with untreated animals), reduces H2S deficiency in the kidneys (H2S level increases by 27.9 %, p˂0.001), increases the activity of H2S-producing enzymes and TRR (by 15.2–60.0 %, p˂0.05), and also reduces the rate of H2S utilization (by 32.7 %, p˂0.001). The introduction of the donor H2S – NaHS potentiates the hypoglycemic activity of metformin and its ability to correct H2S exchange in the kidneys while the introduction of the inhibitor of H2S synthesis – PPG reveals the opposite effect in ST-diabetes.
Conclusion. Metformin exhibits hypoglycemic activity and corrects impaired H2S metabolism in the kidneys in ST-diabetes. The use of NaHS enhanced the hypoglycemic activity of metformin and potentiated its effect on the renal H2S system in the kidneys while the use of PPG reduced the ability of metformin to correct hyperglycemia and renal H2S metabolism in the kidneys.
References
Sun, H.J., Wu, Z.Y., Cao, L., Zhu, M.Y., Liu, T.T. … Bian J.S. (2019). Hydrogen sulfide: Recent progression and perspectives for the treatment of diabetic nephropathy. Molecules, 24 (15). DOI: 10.3390/molecules24152857.
Maheshwari, R.A., Balaraman, R., Sen, A.K., & Seth, A.K. (2014). Effect of coenzyme Q10 alone and its combination with metformin on streptozotocin-nicotinamide-induced diabetic nephropathy in rats. Indian J. Pharmacol., 46 (6), 627-632. DOI: 10.4103/0253-7613.144924.
Kawanami, D., Takashi, Y., & Tanabe, M. (2020). Significance of metformin use in diabetic kidney disease. Int. J. Mol. Sci., 21 (12). DOI: 10.3390/ijms21124239.
Beck, K.F., & Pfeilschifter, J. (2022). The pathophysiology of H2S in renal glomerular diseases. Biomolecules, 12 (2). DOI: 10.3390/biom12020207.
Feng, J., Lu, X., Li, H., & Wang, S. (2022). The roles of hydrogen sulfide in renal physiology and disease states. Ren. Fail, 44 (1), 1289-1308. DOI: 10.1080/ 0886022X.2022.2107936.
Li, L., Xiao, T., Li, F., Li, Y., Zeng, O., … Yang, J. (2017). Hydrogen sulfide reduced renal tissue fibrosis by regulating autophagy in diabetic rats. Mol. Med. Rep., 16 (2),1715-1722. DOI: 10.3892/mmr.2017.6813. Epub 2017 Jun 20.
Hashmi, S.F., Rathore, H.A., Sattar, M.A., Johns, E.J., Gan, C.Y., Chia, T.Y., & Ahmad, A. (2021). Hydrogen sulphide treatment prevents renal ischemia-reperfusion injury by inhibiting the expression of ICAM-1 and NF-kB concentration in normotensive and hypertensive rats. Biomolecules, 11 (10). DOI: 10.3390/biom11101549.
Wiliński B., Wiliński J., Somogyi E., Piotrowska J. & Góralska M. (2011). Amlodipine affects endogenous hydrogen sulfide tissue concentrations in different mouse organs. Folia Med. Cracov., 51 (1-4), 29-35.
Melnik A.V., & Pentiuk, O.O. (2009). Activity of hydrogen sulfide production enzymes in kidneys of rats. Ukrainian Biochemical Journal, 81 (4), 12-23 [in Ukrainian].
Zaichko, N.V., Olkhovskyi, O.S., Yurchenko, P.O., Melnyk, A.V., & Shtatko, O.I. (2013). Method for determination of utilization of hydrogen sulfide in animal organs (Patents of Ukraine for utility models № 87884). State intellectual property service of Ukraine. https://base.uipv.org/searchINV/search.php?action=viewdetails&IdClaim=197439 [in Ukrainian].
Jung, H.I., Lim, H.W., Kim, B.C., Park, E.H., & Lim, C.J. (2004). Differential thioredoxin reductase activity from human normal hepatic and hepatoma cell lines. Yonsei Medical Journal, 45 (2), 263-272. DOI: 10.3349/ymj.2004.45.2.263
Lowry, O.H., Rosebrough, N.J., Farr, A.L., & Randall, R.J. (1951). Protein measurement with the Folin phenol reagent. The Journal of Biological Chemistry, 193 (1), 265-275. https://www.jbc.org/article/S0021-9258(19)52451-6/pdf
Wiliński, B., Wiliński, J., Somogyi, E., Piotrowska, J., & Opoka, W. (2013). Metformin raises hydrogen sulfide tissue concentrations in various mouse organs. Pharmacol. Rep., 65 (3), 737-742. DOI: 10.1016/s1734-1140(13)71053-3.
Hussain Lodhi, A., Ahmad, F.U., Furwa, K., & Madni, A. (2021). Role of oxidative stress and reduced endogenous hydrogen sulfide in diabetic nephropathy. Drug Des. Devel., 15, 1031-1043. DOI: 10.2147/DDDT.S291591.
Bahadoran, Z., Jeddi, S., Mirmiran, P., Kashfi, K., Azizi, F., & Ghasemi, A. (2022). Association between serum hydrogen sulfide concentrations and dysglycemia: a population-based study. BMC Endocr. Disord., 22 (1). DOI: 10.1186/s12902-022-00995-8.
Bełtowski, J., & Jamroz-Wis´niewska, A. (2017). Hydrogen sulfide in the adipose tissue – physiology, pathology and a target for pharmacotherapy. Molecules, 22. DOI: 10.3390/molecules22010063.
Liu, Y., Zhao, H., Qiang, Y., Qian, G., Lu, S. … Fu, Y. (2015). Effects of hydrogen sulfide on high glucose-induced glomerular podocyte injury in mice. Int. J. Clin. Exp. Pathol., 8 (6), 6814-6820.
Ding, T., Chen, W., Li, J., Ding, J., Mei, X., & Hu, H. (2017). High glucose induces mouse mesangial cell overproliferation via inhibition of hydrogen sulfide synthesis in a TLR-4-dependent manner. Cell Physiol. Biochem., 41 (3), 1035-1043. DOI: 10.1159/000461483.
Kundu, S., Pushpakumar, S., Khundmiri, S. J., & Sen, U. (2014). Hydrogen sulfide mitigates hyperglycemic remodeling via liver kinase B1-adenosine monphosphate-activated protein kinase signaling. Biochim. Biophys. Acta, 1843 (12), 2816-2826. DOI: 10.1016/j.bbamcr.2014.08.005.
Chang, G.Q., Bai, S.Z., Sun, F.Q., Wu, R., Wei, C. … Li, H.Z. (2022). SKF38393 prevents high glucose (HG)-induced endothelial dysfunction by inhibiting the effects of HG on cystathionine γ-lyase/hydrogen sulfide activity and via a RhoA/ROCK1 pathway. Front Biosci (Landmark Ed), 27 (2). DOI: 10.31083/j.fbl2702049.
Gheibi, S., Jeddi, S., Kashfi, K., & Ghasemi, A. (2019). Effects of hydrogen sulfide on carbohydrate metabolism in obese type 2 diabetic rats. Molecules, 24 (1). DOI: 10.3390/molecules24010190.
Xue, H., Yuan, P., Ni, J., Li, C., Shao, D. … Lu L. (2013). H(2)S inhibits hyperglycemia-induced intrarenal renin-angiotensin system activation via attenuation of reactive oxygen species generation. PLoS One, 8 (9). DOI: 10.1371/journal.pone.0074366.
Zhang, H., Huang, Y., Chen, S., Tang, C., Wang, G. … Jin, H. (2020). Hydrogen sulfide regulates insulin secretion and insulin resistance in diabetes mellitus, a new promising target for diabetes mellitus treatment? A review. J. Adv. Res., 26, 19-30. DOI: 10.1016/j.jare.2020.02.013.
Xu, M., Liu, X., Bao, P., Wang, Y., Zhu, X. … Lu J. (2022). Skeletal Muscle CSE Deficiency Leads to Insulin Resistance in Mice. Antioxidants (Basel), 11 (11).DOI: 10.3390/antiox11112216.
Zhu, L., Yang, B., Ma, D., Wang, L., & Duan, W. (2020). Hydrogen sulfide, adipose tissue and diabetes mellitus. Diabetes Metab. Syndr. Obes., 13, 1873-1886. DOI: 10.2147/DMSO.S249605.
Parsanathan, R., & Jain, S.K. (2022). Hydrogen sulfide regulates irisin and glucose metabolism in myotubes and muscle of HFD-fed diabetic mice. Antioxidants (Basel), 11 (7). DOI: 10.3390/antiox11071369.
Dugbartey, G.J., Alornyo, K.K., Adams, I., Atule, S., Obeng-Kyeremeh, R. … Adjei S. (2022). Targeting hepatic sulfane sulfur/hydrogen sulfide signaling pathway with α-lipoic acid to prevent diabetes-induced liver injury via upregulating hepatic CSE/3-MST expression. Diabetol. Metab. Syndr., 14 (1). DOI: 10.1186/s13098-022-00921-x.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 Medical and Clinical Chemistry
This work is licensed under a Creative Commons Attribution 4.0 International License.
