Recurrent insulin-induced hypoglycemia induces AngII and COX2 leading to renal (pro)renin receptor expression and oxidative stress

  • Authors

    • Wael Alanazi ULM College of Pharmacy
    • Mohammad Uddin ULM College of Pharmacy
    • Selim Fakhruddin ULM College of Pharamcy
    • Keith Jackson ULM College of Pharmacy
    2017-02-25
    https://doi.org/10.14419/ijm.v5i1.6858
  • Angiotensin II (AngII), Cyclooxygenase-2 (COX2), (Pro) Renin Receptor (PRR), Oxidative Stress, Recurring Insulin-Induced Hypoglycemia (RIIH).
  • Background: Recurrent insulin-induced hypoglycemia (RIIH) is an avoidable consequence in the therapeutic management of diabetes mellitus. RIIH has been implicated in causing hypertension through an increase in renal and systemic AngII production.

    Objective: The present study was performed to assess the hypothesis that chronic insulin treatment enhances AngII and COX2 formation which in turn increases (pro) renin receptor (PRR) expression and NADPH oxidase-mediated oxidative stress, leading to renal and cardiac injury.

    Methods: The present studies were conducted in Male Sprague Dawley rats treated with daily subcutaneous injections of 7u/kg insulin or saline for 14 days. On the 14th day, surgery was performed for treatment infusion (captopril 12mg/kg, NS398 0.3mg/kg or vehicle), and renal interstitial fluid sample and urine collections for biomarker measurements. At the end of the experiments, kidneys and hearts were harvested to evaluate PRR and NOX2 (NADPH oxidase subunit) expression and oxidative stress.

    Results: We found that RIIH enhanced AngII and COX2 activity, leading to renal PRR expression and NADPH oxidase-induced oxidative stress in the heart and kidney. 8-isoprostane was evaluated as a renal biomarker of oxidative stress, which was induced in insulin treated animals and modulated by captopril and NS398. In addition, there was a slight increase in NGAL, a urinary biomarker of acute kidney injury (AKI), in insulin treated animals when compared to control.

    Conclusion: These results demonstrate that RIIH induces renal PRR expression and oxidative stress through increasing AngII and COX2 in the heart and kidney, leading to end-organ damage.

  • References

    1. [1] Advani A, Kelly DJ, Cox AJ, White KE, Advani SL, Thai K, Connelly KA, Yuen D, Trogadis J, Herzenberg AM, Kuliszewski MA, Leong-Poi H & Gilbert RE (2009) The (Pro)renin receptor: site specific and functional linkage to the vacuolar H+-ATPase in the kidney. Hypertension. 54, 261–269. https://doi.org/10.1161/HYPERTENSIONAHA.109.128645.

      [2] Alanazi W, Fakhruddin S & Jackson KE (2016) Microdialysis Sampling of Renal Interstitial Fluid in Acute Studies. International Journal of Biology 8, 69-79. https://doi.org/10.5539/ijb.v8n1p69.

      [3] Baltatzi M, Savopoulos C & Hatzitolios A (2011) Role of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in hypertension of chronic kidney disease and renoprotection. Study results. Hippokratia 15, 27-32.

      [4] Bergendi L, Benes L, Duracková Z & Ferencik M (1999) Chemistry, physiology and pathology of free radicals. Life Sci. 65, 1865-74. https://doi.org/10.1016/S0024-3205(99)00439-7.

      [5] Bhardwaj SK, Sharma ML, Gulati G, Chhabra A, Kaushik R, Sharma P & Kaur G (1998) Effect of starvation and insulin-induced hypoglycemia on oxidative stress scavenger system and electron transport chain complexes from rat brain, liver, and kidney. Mol Chem Neuropathol. 34, 157-68. https://doi.org/10.1007/BF02815077.

      [6] Cheng SE, Lee IT, Lin CC, Wu WL, Hsiao LD & Yang CM (2013) ATP mediates NADPH oxidase/ROS generation and COX-2/PGE2 expression in A549 cells: role of P2 receptor-dependent STAT3 activation. PLoS One. 8, e54125. https://doi.org/10.1371/journal.pone.0054125.

      [7] Cracowski JL, Durand T & Bessard G (2002) Isoprostanes as a biomarker of lipid peroxidation in humans: physiology, pharmacology and clinical implications. Trends Pharmacol Sci. 23, 360-6. https://doi.org/10.1016/S0165-6147(02)02053-9.

      [8] Cryer PE (2004) Current concepts: Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 350, 2272–9. https://doi.org/10.1056/NEJMra031354.

      [9] Deng A, Tang T, Singh P, Wang C, Satriano J, Thomson SC & Blantz RC (2009) Regulation of oxygen utilization by angiotensin II in chronic kidney disease. Kidney Int. 75, 197-204. https://doi.org/10.1038/ki.2008.481.

      [10] Desouza CV, Bolli GB & Fonseca V (2010) Hypoglycemia, diabetes, and cardiovascular events. Diabetes Care. 33, 1389-94. https://doi.org/10.2337/dc09-2082.

      [11] Devarajan P (2010) Neutrophil gelatinase-associated lipocalin: a promising biomarker for human acute kidney injury. Biomark Med. 4, 265–280. https://doi.org/10.2217/bmm.10.12.

      [12] Dikalov S, Griendling KK & Harrison DG (2007) Measurement of reactive oxygen species in cardiovascular studies. Hypertension. 49, 717-727. https://doi.org/10.1161/01.HYP.0000258594.87211.6b.

      [13] Dikalov SI & Nazarewicz RR (2013) Angiotensin II-induced production of mitochondrial reactive oxygen species: potential mechanisms and relevance for cardiovascular disease. Antioxid Redox Signal. 19, 1085-94. https://doi.org/10.1089/ars.2012.4604.

      [14] Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev. 82, 47-95. https://doi.org/10.1152/physrev.00018.2001.

      [15] Finkel T (2011) Signal transduction by reactive oxygen species. J Cell Biol. 194, 7-15. https://doi.org/10.1083/jcb.201102095.

      [16] Fiorentino TV, Prioletta A, Zuo P & Folli F (2013) Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Curr Pharm Des. 19, 5695-703. https://doi.org/10.2174/1381612811319320005.

      [17] Fisher BM, Gillen G, Hepburn DA, Dargie HJ & Frier BM (1990) Cardiac responses to acute insulin-induced hypoglycemia in humans. Am J Physiol. 258, H1775-9.

      [18] Giacco F & Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res. 107, 1058–1070. http://dx.doi.org/10.1161/CIRCRESAHA.110.223545.

      [19] Green T, Gonzalez AA, Mitchell KD & Navar LG (2012) The complex interplay between cyclooxygenase-2 and angiotensin II in regulating kidney function. Curr Opin Nephrol Hypertens. 21, 7-14. https://doi.org/10.1097/MNH.0b013e32834d9d75.

      [20] Gupta V, Bhinge KN, Hosain SB, Xiong K, Gu X, Shi R, Ho MY, Khoo KH, Li SC, Li YT, Ambudkar SV, Jazwinski SM, Liu YY (2012) Ceramide glycosylation by glucosylceramide synthase selectively maintains the properties of breast cancer stem cells. J Biol Chem. 287, 37195-205. https://doi.org/10.1074/jbc.M112.396390.

      [21] Haces ML, Montiel T & Massieu L (2010) Selective vulnerability of brain regions to oxidative stress in a non-coma model of insulin-induced hypoglycemia. Neuroscience 165, 28–38. https://doi.org/10.1016/j.neuroscience.2009.10.003.

      [22] Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol. 11, 298-300. https://doi.org/10.1093/geronj/11.3.298.

      [23] Hernández J, Astudillo H & Escalante B (2002) Angiotensin II stimulates cyclooxygenase-2 mRNA expression in renal tissue from rats with kidney failure. Am J Physiol Renal Physiol. 282, F592-8. https://doi.org/10.1152/ajprenal.00194.2001.

      [24] Hernanz R, Briones AM, Salaices M & Alonso MJ (2014) new roles for old pathways? A circuitous relationship between reactive oxygen species and cyclo-oxygenase in hypertension. Clin Sci (Lond). 126, 111-21. https://doi.org/10.1042/CS20120651.

      [25] Hu ZW, Kerb R, Shi XY, Wei-Lavery T & Hoffman BB (2002) Angiotensin II increases expression of cyclooxygenase-2: implications for the function of vascular smooth muscle cells. J Pharmacol Exp Ther. 303, 563-573. https://doi.org/10.1124/jpet.102.037705.

      [26] Ichihara A, Sakoda M, Kurauchi-Mito A, Kaneshiro Y & Itoh H (2008) Involvement of (pro)renin receptor in the glomerular filtration barrier. J Mol Med. 86, 629–635. https://doi.org/10.1007/s00109-008-0327-1.

      [27] Imig JD (2006) Eicosanoids and renal vascular function in diseases. Clin Sci. 111, 21-34. https://doi.org/10.1042/CS20050251.

      [28] Kalra S, Mukherjee JJ, Venkataraman S, Bantwal G, Shaikh S, Saboo B, Das AK & Ramachandran A (2013) Hypoglycemia: The neglected complication. Indian J Endocrinol Metab. 17, 819-34. https://doi.org/10.4103/2230-8210.117219.

      [29] King AJ & Fink GD (2006) Chronic low-dose angiotensin II infusion increases venomotor tone by neurogenic mechanisms. Hypertension. 48, 927-33. https://doi.org/10.1161/01.HYP.0000243799.84573.f8.

      [30] Kunsch C & Medford RM (1999) Oxidative stress as a regulator of gene expression in the vasculature. Circ Res. 85, 753-66. https://doi.org/10.1161/01.RES.85.8.753.

      [31] Li W, Peng H, Cao T, Sato R, McDaniels SJ, Kobori H, Navar LG & Feng Y (2012) Brain-targeted (pro)renin receptor knockdown attenuates angiotensin II-dependent hypertension. Hypertension. 59, 1188-94. https://doi.org/10.1161/HYPERTENSIONAHA.111.190108.

      [32] Liu FY, Liu XY, Zhang LJ, Cheng YP, Jiang YN (2014) Binding of prorenin to (pro)renin receptor induces the proliferation of human umbilical artery smooth muscle cells via ROS generation and ERK1/2 activation. J Renin Angiotensin Aldosterone Syst. 15, 99-108. https://doi.org/10.1177/1470320314525215.

      [33] McGowan JE, Chen L, Gao D, Trush M & Wei C (2006) Increased mitochondrial reactive oxygen species production in newborn brain during hypoglycemia. Neurosci Lett. 399, 111–114. https://doi.org/10.1016/j.neulet.2006.01.034.

      [34] Nguyen G, Delarue F, Berrou J, Rondeau E & Sraer JD (1996) Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen. Kidney Int. 50, 1897–1903. https://doi.org/10.1038/ki.1996.511.

      [35] Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T & Sraer JD (2002) Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest. 109, 1417–27. https://doi.org/10.1172/JCI0214276.

      [36] Pà ramo B, Hernandez-Fonseca K, Estrada-Sanchez AM, Jimenez N, Hernandez-Cruz A & Massieu L (2010) Pathways involved in the generation of reactive oxygen and nitrogen species during glucose deprivation and its role on the death of cultured hippocampal neurons. Neuroscience 167, 1057–1069. https://doi.org/10.1016/j.neuroscience.2010.02.074.

      [37] Paranjape SA & Briski KP (2005) recurrent insulin-induced hypoglycemia causes site-specific patterns of habituation or amplification of CNS neuronal genomic activation. Neuroscience 130, 957-70. https://doi.org/10.1016/j.neuroscience.2004.09.030.

      [38] Pavelescu LA (2015) on reactive oxygen species measurement in living systems. J Med Life. 8, 38-42.

      [39] Popolo A, Autore G, Pinto a & Marzocco S (2013) Oxidative stress in patients with cardiovascular disease and chronic renal failure. Free Radic Res. 47, 346-56. https://doi.org/10.3109/10715762.2013.779373.

      [40] Prathipati P, Alanazi W, Fakhruddin, Jackson DW & Jackson KE (2015) Role of interstitial angiotensin II and ATP in mediating renal injury induced by recurrent insulin induced hypoglycemia. Annual Research & Review in Biology 6, 328-36. https://doi.org/10.9734/ARRB/2015/16184.

      [41] Pruchniak MP, Araźna M & Demkow U (2016) Biochemistry of Oxidative Stress. Adv Exp Med Biol. 878, 9-19. https://doi.org/10.1007/5584_2015_161.

      [42] Quadri S, Prathipati P, Jackson DW & Jackson KE (2013) Augmentation of heme oxygenase promotes acute angiotensin II induced hypertenion. Clinical and experimental medical sciences 1, 21-43. https://doi.org/10.12988/cems.2013.13003.

      [43] Quadri S, Prathipati P, Jackson DW & Jackson KE (2014) Hemodynamic consequences of recurrent insulin-induced hypoglycemia. Clin Exp Pharmacol Physiol. 41, 81-8. https://doi.org/10.1111/1440-1681.12183.

      [44] Rajagopalan S, Kurz S, Münzel T, Tarpey M, Freeman BA, Griendling KK & Harrison DG (1996) Angiotensin II mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 97, 1916-23. https://doi.org/10.1172/JCI118623.

      [45] Ratliff BB, Sekulic M, Rodebaugh J & Solhaug MJ (2010) Angiotensin II regulates NOS expression in afferent arterioles of the developing porcine kidney. Pediatr Res. 68, 29-34. https://doi.org/10.1203/PDR.0b013e3181e12770.

      [46] Razavi Nematollahi L, Kitabchi AE, Stentz FB, Wan JY, Larijani BA, Tehrani MM, Gozashti MH, Omidfar K & Taheri E (2009) Proinflammatory cytokines in response to insulin-induced hypoglycemic stress in healthy subjects. Metabolism. 58, 443-8. https://doi.org/10.1016/j.metabol.2008.10.018.

      [47] Schrader L, Kinzenbaw DA, Johnson AW, Faraci FM & Didion SP (2007) IL-6 deficiency protects against angiotensin II induced endothelial dysfunction and hypertrophy. Arterioscler Thromb Vasc Biol. 27, 2576-81. https://doi.org/10.1161/ATVBAHA.107.153080.

      [48] Shafiee G, Mohajeri-Tehrani M, Pajouhi M & Larijani B (2012) The importance of hypoglycemia in diabetic patients. J Diabetes Metab Disord. 11, 17. https://doi.org/10.1186/2251-6581-11-17.

      [49] Suh SW, Gum ET, Hamby AM, Chan PH & Swanson RA (2007) Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase. J Clin Invest. 117, 910-8. https://doi.org/10.1172/JCI30077.

      [50] The DCCT Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long term complication in insulin-dependent diabetes mellitus. N Engl J Med. 329, 977-86. https://doi.org/10.1056/NEJM199309303291401.

      [51] The DCCT Research Group (1997) Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes. 46, 271–86. https://doi.org/10.2337/diab.46.2.271.

      [52] Tian XY, Wong WT, Leung FP, Zhang Y, Wang YX, Lee HK, Ng CF, Chen ZY, Yao X, Au CL, Lau CW, Vanhoutte PM, Cooke JP & Huang Y (2012) Oxidative stress-dependent cyclooxygenase-2-derived prostaglandin F2α impairs endothelial function in renovascular hypertensive rats. Antioxid. Redox Signaling 16, 363-73. https://doi.org/10.1089/ars.2010.3874.

      [53] Toda N, Ayajiki K & Okamura T (2007) Interaction of endothelial nitric oxide and angiotensin in the circulation. Pharmacol Rev. 59, 54-87. https://doi.org/10.1124/pr.59.1.2.

      [54] Touyz RM & Schiffrin EL (1999) Ang II-stimulated superoxide production is mediated via phospholipase D in human vascular smooth muscle cells. Hypertension. 34, 976-82. https://doi.org/10.1161/01.HYP.34.4.976.

      [55] Van der Giet M, Erinola M, Zidek W & Tepel M (2002) Captopril and quinapril reduce reactive oxygen species. Eur J Clin Invest. 32, 732-7. https://doi.org/10.1046/j.1365-2362.2002.01064.x.

      [56] Wang F, Lu X, Peng K, Du Y, Zhou SF, Zhang A, Yang T (2014) Prostaglandin E-prostanoid4 receptor mediates angiotensin II-induced (pro) renin receptor expression in the rat renal medulla. Hypertension. 64, 369-77. https://doi.org/10.1161/HYPERTENSIONAHA.114.03654.

      [57] Wei Y, Sowers JR, Nistala R, Gong H, Uptergrove GM, Clark SE, Morris EM, Szary N, Manrique C & Stump CS (2006) Angiotensin II-induced NADPH oxidase activation impairs insulin signaling in skeletal muscle cells. J Biol Chem. 281, 35137-46. https://doi.org/10.1074/jbc.M601320200.

      [58] Wong WT, Tian XY, Chen Y, Leung FP, Liu L, Lee HK, Ng CF, Xu A, Yao X, Vanhoutte PM, Tipoe GL & Huang Y (2010) Bone morphogenic protein-4 impairs endothelial function through oxidative stress-dependent cyclooxygenase-2 upregulation: implications on hypertension. Circ. Res. 107, 984-91. https://doi.org/10.1161/CIRCRESAHA.110.222794.

      [59] Wright RJ & Frier BM (2008) vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev. 24, 353-63. https://doi.org/10.1002/dmrr.865.

      [60] Wu R, Laplante MA & de Champlain J (2005) Cyclooxygenase-2 inhibitors attenuate angiotensin II-induced oxidative stress, hypertension, and cardiac hypertrophy in rats. Hypertension. 45, 1139-44. https://doi.org/10.1161/01.HYP.0000164572.92049.29.

      [61] Yang H, Jin X, Kei Lam CW & Yan SK (2011) Oxidative stress and diabetes mellitus. Clin Chem Lab Med. 49, 1773-82. https://doi.org/10.1515/cclm.2011.250.

      [62] Yang T (2015) Crosstalk between (Pro) renin receptor and COX-2 in the renal medulla during angiotensin II-induced hypertension. Curr Opin Pharmacol. 21, 89-94. https://doi.org/10.1016/j.coph.2014.12.011.

      [63] Zhang C, Hein TW, Wang W & Kuo L (2003) Divergent roles of angiotensin II AT1 and AT2 receptors in modulating coronary microvascular function. Circ Res. 92, 322-9. https://doi.org/10.1161/01.RES.0000056759.53828.2C.

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    Alanazi, W., Uddin, M., Fakhruddin, S., & Jackson, K. (2017). Recurrent insulin-induced hypoglycemia induces AngII and COX2 leading to renal (pro)renin receptor expression and oxidative stress. International Journal of Medicine, 5(1), 71-78. https://doi.org/10.14419/ijm.v5i1.6858