Acta Scientific Pharmaceutical Sciences

Editorial Volume 1 Issue 3

Bradykinin Status in Type 2 Diabetes

Jagdish N Sharma*

Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Health Sciences Centre, Kuwait University, Safat, Kuwait

*Corresponding Author: Jagdish N Sharma, Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Health Sciences Cen- tre, Kuwait University, Safat, Kuwait.

Received: June 17, 2017; Published: August 01, 2017

Citation: Jagdish N Sharma .“Bradykinin Status in Type 2 Diabetes”. Acta Scientific Pharmaceutical Sciences 1.3 (2017).

The Bradykinin System

  The kinins are pharmacologically active polypeptides, which are released in the tissues and body fluids as a result if the enzymatic action of kallikreins on kininogens. The kinin family includes BK (Arg-Pro-Pro-gly-Phe-Ser-Pro-Phe-Arg), kallidin (Lys- -Arg-Pro- Pro-Gly-Phe-Ser-Pro-Phe-Arg) and methionyl-lysyl-BK (Met-Lys- Arg-Pro-Pro-Gly-Phe-Arg). Kallidin and methionyl-lysyl-BK are converted into BK by aminopeptidases present in plasma and urine [1]. Kinins are rapidly (< 15 sec) inactivated by circulating kininases [2].

  Kininogens are multifunctional proteins derived mainly from alpha -2 globulins. In humans, the two forms of kininogens are; high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK) [3].

  These kininogens vary from each other’s in molecular weight, susceptibility to plasma and tissue kallikreins and in their physiological properties [4]. They are synthesized in the liver and circulate in the plasma and other body fluids. In addition, there is a T-kininogen in the rat plasma, which is considered to be an acute phase reactant of inflammation [5]. This kininogen releases T-kinin by the enzymatic action of T- kallikrein in rats [6]. Tissue kallikrein is found in various organs such as the kidney, heart and synovial tissue [7,8]. These kallikreins differ from one another in molecular weight, biological function, physicochemical and immunological properties [9]. The tissue kallikrein is synthesized in the cells as a precursor and converted into active form by the cleavage of an amino terminal peptide [10]. Active tissue kallikrein acts on LMWK to release kallidin. The plasma kallikrein is found in circulation in an inactive form, which is known as prekallikrein or Fletcher factor[11]. This inactive prekallikrein is converted to active kallikrein by activated hageman factor (XIIa). In addition, plasma kallikrein is able to convert inactive factor XII to XIIa by positive feedback reac- tion. The plasma prekallikrein and HMWK are present together in a complex form [12]. Factor XIIa and factor XI circulate with HMWK in bound form [13]. In this way, factor XI can be converted into XIa for the participation in the intrinsic coagulation cascade [14]. In immunological reactions, the tissue proteoglycone and mast cell heparin might act as an initiating surface for initial activation of the Hageman factor [15]. It seems that the kinins may be generated in parallel with the formation of thrombin at inflammatory sites, since inactive plasma kallikrein can be activated by coagulant Hageman factor. The tissue kallikrein multigene family comprises a closely related cluster of genes that vary in number between the different mammalian species: 24 genes have been identified in the mouse, 20 in the rat, 3 in humans and 3 in the hamster [9].

  Several restriction fragment length polymorphisms (RFLP) has been mapped in tissue kallikrein gene and their regulatory regions in spontaneously hypertensive rats (SHR) [16]. These findings may reflect a possible difference in the tissue kallikrein gene locus between SHR and normotensive Wistar-Kyoto rats (WKYR). A tissue kallikrein RFLP has been indicated to cosegregate with high BP in the F2 offspring of SHR and normotensive Brown Norway rats crosses [17]. This finding strongly suggests a possibility of SHR. The kininases, kinin inactivating enzymes, are present in the plasma, endothelial cells and in the tissues to regulate the physiological functions of the kinins in the body. These are known as kininase I, Kininase II or angiotensin converting enzyme (ACE) and enkaphalinase. In plasma, kininase I cleaves the C-terminal arginine of BK to form des-Arg9-BK [18] . Kininase II causes inactivation of BK by releasing pentapeptide (Arg-Pro-Pro-Gly-Phe0 and tripeptide (Ser-Pro-Phe) fragments.

Figure 1: shows the bradykinin formation, activation and inhibition pathways.

Figure 1: shows the bradykinin formation, activation and inhibition pathways.

The Bradykinin System and Diabetes

  Diabetes has been implicated as a major risk factor in the development of cardiovascular and renal complications. Previous studies have indicated altered activities of the bradykinin-forming components [19] in diabetic patients and experimental animals.High prevalence rates (25%) of diabetes have been documented in Kuwaiti population [20]. Type2 diabetes can lead to hypertension, renal and cardiac complications resulting in high rates of mortality worldwide and in Kuwait as well. Bradykinin (BK), a pharmacologically active polypeptide, is one of kinins which is released in the tissues and body fluids as a result of enzymatic action of kallikreins on kininogens. The two types of kallikrein are tissue kallikrein and plasma kallikrein. Plasma kallikrein is also present in inactive form known as prekallikrein, which can be activated into kallikrein. Tissue kallikrein is mainly expressed in the kidney (urine), glandular tissue, vasculature, [21] heart and brain. It preferentially acts on low molecular weight kininogen substrate to release lysyl-BK. Tissue kallikrein has also been reported to be present in plasma [22,23] Plasma kallikrein preferentially acts on high molecular weight kininogen substrate to release BK. BK promotes both cardiovascular and renal functions, for example, vasodilation, naturesis and diuresis [24,25] BK is rapidly (< 15 sec) inactivated by circulating kinases [26] BK acts on B1receptor (B1R) and B2 receptor (B2R)[27] to elicit physiological and pharmacological actions. It has been shown previously that type 1 diabetic patients are at a risk of developing nephropathy, having increased renal tissue kallikrein and BK levels [28]. In addition, raised plasma prekallikrein levels in type 1 diabetes has been considered as a risk marker for hypertension and nephropathy [29]. It has been shown that diabetic rats with moderate hyperglycemia, in association with increased urinary kallikrein excretion, resulted in reduced renal vascular resistance (RVR) and increased both renal plasma flow (RPF) and glomerular filtration rate (GFR) [28,29].

  The contribution of the renal BK-forming components has been implicated in the renal injury [30] in experimental and type 1 diabetes. The urinary and plasma BK-forming components are comprised of proteins that mediate their effects on vasculature by releasing BK [30-33]. It is also known that the tissue kallikrein present in the urine is originating from the kidney and it reflects the renal activity of BK [9]. Higher concentrations of prekallikrein levels may suggest the onset of renal abnormalities. In fact, high plasma prekallikrein levels have been documented in type 1 diabetic patients [27]. These investigators suggested that increased plasma prekallikrein level could be a risk factor for hypertension and nephropathy in type 1 diabetes. The present study may also suggest a similar mechanism for developing hypertension and nephropathy in type 2 diabetic patients. Therefore, plasma prekallikrein could be a useful tool for monitoring diabetic patients for developing hypertension and/or renal abnormalities.

  It is of interest to suggest that the early detection of type 2 diabetes based on high urinary kallikrein would be an indicator for future renal abnormality that can be prevented with the treatment. In addition, high plasma prekallikrein activity may serve as an indicator for causing hypertension and left ventricular hypertrophy in dia- betic rats [34].

  On the other hand, we observed reduced levels of total urinary kininogen in type 2 diabetic patients. This observation might be a reflection on the utilization of kininogen to form BK, a proinflammatory agent as previously reported [35,36]. BK1R and BK2R antagonists may normalize the diabetic state in experimentally induced diabetes in mice [37]. Thus, BK antagonist may be targeted for use in diabetic disorders. Moreover, high levels of tissue kallikrein could diminish glucose transport to the tissue [22]. This may also suggest that high levels of tissue kallikrein in diabetic patients might be a predisposing factor in the induction of type 2 diabetes due to the inhibition of glucose transfer to the tissues [38]. Plasma levels of tissue kallikrein have been reported to be increased in type 2 diabetes as previously reported [15,39]. In the present study however, we also observed high concentrations of plasma tissue kallikrein, which presumably be due to the hyperactivity of the BK-forming system to induce systemic metabolic abnormalities. It has been reported that tissue kallikrein activates B2R directly without BK generation [40]. Furthermore, diabetic rats have been shown to have the glomerular B1R and B2R expression in the diabetic state [41]. Thus, BK system has significant role in the genesis of type 2 diabetes and agents that participates in the BK pathways regulation may be valuable in the development of diabetes [42-54].

Bibliography

  1. Nolly HL and Brotis J. “Kinin- forming enzyme in rat cardiac tissue”. American Journal of Physiology 265 (1981): H1209- H1214.
  2. Sharma JN and K Uma. “Cardiac kallikrein in hypertensive and diabetic rats with and without diabetes”. Immunopharmacology 33 (1996): 341-343.
  3. Sharma JN.,et al. “Left ventricular hypertrophy and its relation to the cardiac kinin- forming system in hypertensive and diabetic rats”. International Journal of Cardiology 63.3 (1998): 229-235..
  4. Sharma JN., et al. “Altered cardiac tissue and plasma kininogen levels in hypertensive and diabetic rats”.Immunopharmacology 43 (1999): 129-132.
  5. Oza NB and Goud HD. “Kiniogeses of the aortic wall in spontaneouly hypertensive rats”.Journal of Cardiovascular Pharmacology 20.9 (1992): 1-3
  6. HL Nolly., et al. “Kallikrein release by vascular tissue”. American Journal of Physiology 265 (1993): H1209-H1214.
  7. A Vegh., et al. “Local intracoronary infusions of bradykinin profoundly reduce the severity of ischaemia- induced arrhythmia in anaesthetized dogs”.British Journal of Pharmacology 104.2 (1991): 294-295.
  8. W Linz., et al. “Bradykinin prevent left ventricular hypertrophy in rats”. Journal of Hypertension 11.5 (1993): S96-S97.
  9. A Vegh., et al. “Attenuation of the antiarrhythmic effects of ischaemia preconditioning by blocked of bradykinin B2 receptors”. British Journal of Pharmacology 113.4 (1994): 1167-1172.
  10. TM Walls., et al. “Role of bradykinin in myocardial preconditioning”. Journal of Pharmacology and Experimental Therapeutics 270.2 (1994): 681-689.
  11. W Linz W.,et al. “Contribution of bradykinin to the cardiovascular effects of Ramipril”. Journal of Cardiovascular Phar amacology 22.9 (1993): S1-S8.
  12. JN Sharma. “Kinin- forming system in the genesis of hypertension”. Agents and Actions 14.2 (1984): 200-205.
  13. JN Sharma. “Interrelationship between the kallikrein- kinin system and hypertension: a review”. General Pharmacology 19.2 (1988):177-187.
  14. JN Sharma. “Contribution of kinin system to the antihyper tensive action of angiotensin converting enzyme inhibitors”. Advances in Experimental Medicine and Biology 247A (1989):197- 205.
  15. JN Sharma.,et al. “Blood pressure regulation by the kalli-krein- kinin system”. General Pharmacology 27.1 (1996): 55-63.
  16. JN Sharma. “Does kinin mediate the hypotensive action of angiotensin converting enzyme (ACE) inhibitors”. General Pharmacology 21.4 (1990): 451-457.
  17. JN Sharma. “Involvement of the kinin- forming system in physiopathology of rheumatoid inflammation”. Agents and Actions 38(III) (1992): 343-361.
  18. T Nagayasa and S Nagasawa. “Studies of human kininogen. Isolation, characterization, and cleavage by plasma kalli- krein of high molecular weight (HMW) kiniogen”. The Journal of Biochemistry 85.1 (1979): 249-258.
  19. W Muller- Esterl, et al. “Kininogens revisited”. TIBS 11.8 (1986): 336-339.
  20. LM Greenbaum., et al. “children of technology”. Biochemical Pharmacology 33 (1982): 2943-2944.
  21. H Okamoto and LM Greenbaum. “Pharmacological properties of T- kinin”. Biochemical Pharmacology 32.17 (1983): 2637-2638.
  22. K Nustad., et al. “Synthesis of kallikrein by rat kidney slices”.British Journal of Pharmacology 53.2 (1975): 229-234.
  23. JN Sharma., et al. “Detection of tissue kallikrein- like activity in inflamed synovial tissue”. Archives internationales de pharmacodynamie et de thérapie 262.2 (1983): 279-286.
  24. KD Bhoola., et al . “Bioregulation of kinin, kallikrein, kininogen and kininases”. Pharmacological Reviews 44.1 (1992): 1-80.
  25. Takada Y., et al . “Purification of human urinary prokallikrein: identification of the site of activation by the metalioprotinase thermolysin”. Biochemical Journal 232 (1985): 851-856.
  26. Weiss AS., et al . “Fletcher factor deficiency: a diminished rate of Hageman factor activation caused by absence of prekalli - krein with abnormalities of coagulation, fibrinolysis, chemo - tactic activity and kinin generation”. The Journal of Clinical In- vestigation 53.2 (1974): 622-633.
  27. Cochrane CG., et al . “Activation of Hageman factor in solid and fluid phase. A critical role of kallikrein”. The Journal of Experi - mental Medicine 138.6 (1973): 1564-1583.
  28. Griffin JH and Cochrane CG. “Mechanism for the involvement of high molecular weight kininogen in surface- dependent re- actions of Hageman factor”. Proceedings of the National Acad- emy of Sciences 73.8 (1976): 2554-2558.
  29. Manddle R., et al. “Identification of prekallikrein and HMW- kininogen as a complex in human plasma”. Proceedings of the National Academy of Sciences 73.11 (1976): 4176-4183.
  30. Thampson RE.,et al. “Association of factor XI and high molecular weight kininogen in human plasma”. Journal of Clinical In- vestigation 60.6 (1977): 1376-1380.
  31. Leeb-Lundberg LMF., et al. “Classification of the kinin receptor family: From Molecular mechanisms to Pathophysiological consequences. International Union of Pharmacology. XLV”. Pharmacological Reviews 57.1 (2005): 27-77.
  32. Abdella N., et al. “Non-insulin- dependent diabetes in Kuwait: prevalence rates and associated risk factors”. Diabetes Research and Clinical Practice 42.3 (1998): 187-196.
  33. Al-Shoumer KA., et al. “Serum leptin and metabolic variables in Arabs with type 2 diabetes”. Annals of Saudi Medicine 28.5 (2008): 267-370.
  34. Sharma JN. “The tissue kallikrein-kininogen-kinin pathways: role in cardiovascular system”. Archives of Medical Research 37.3 (2006): 299-306.
  35. Rabito SF., et al . “Immunoreactive glandular kallikrein in rat plasma: a radioimmunoassay for its determination”. Ameri- can Journal of Physiology 242.4 (1982): H602-H610
  36. Yayami M., et al . “Tissue kallikrein is synthesized and secret - ed by human vascular endothelial cells”. Biochimica et Bio- physica Acta 1593 (2003): 231-238.
  37. Katori M and Majima M. “A missing link between a high salt intake and blood pressure increase”. Journal of Pharmaco- logical Sciences 100.5 (2006): 370-390.
  38. Sharma JN., et al . “Left ventricular hypertrophy and its rela - tion to cardiac kinin-forming system in hypertensive and dia- betic rats”. International Journal of Cardiology 63.3 (1998): 229-235.
  39. Jaffa AA., et al . “Plasma prekallikrein: a risk marker for hy - pertension and nephropathy in type 1 diabetes”. Diabetes 52.5 (2003): 1215-1221.
  40. Harvey JN., et al . “Renal kallikrein and the hemodynamic abnormalities of the diabetic kidney”. Diabetes 39.3 (1990): 299-303.
  41. Jaffa AA., et al . “Kinin, a mediator of diabetes induced glomer- ular hyper filtration”. Diabetes 44.2 (1995): 156-160.
  42. Parappil A., et al . “Diagnostic criteria for diabetes revisited: making use of combined criteria”. BMC Endocrinol Disorders 2 (2002): 1-7.
  43. Domke I., et al . “Therapeutic drug monitoring on COBAS INTEGRA 400--evaluation results”. Clinical Laboratory 46 (2000): 509-515.
  44. Jaffa AA., et al . “Abnormal regulation of renal kallikrein in experimental diabetes”. Journal of Clinical Investigation 80.6 (1987): 1651-1659.
  45. Jaffa AA., et al . “Renal kallikrein and renin mRNA levels in di - abetes and their induction by insulin and insulin like growth factor 1”. Diabetes 46.12 (1997): 2040-2056.
  46. Sharma JN and Kesavarao U. “Changes in plasma prekallikrein, blood pressure and left ventricular thickness in hypertensive and normotensive diabetic rats”. Methods and Findings in Ex - perimental and Clinical Pharmacology 29.2 (2007): 75-78.
  47. Weinberg MS., et al . “Urinary kininogen: a possible regulator of kinin formation in normal individuals and subjects with essential hypertension, end-satge renal and liver disease”. Advances in Experimental Medicine and Biology 198A (1986): 119-125.
  48. Weinberg MS., et al . “The role of urinary kininogen in regu- lation of kinin generation”. Kidney International 28.6 (1985): 975-981.
  49. Zuccollo A., et al . “Effect of B1 aqnd B2 kinin receptor antag - onists in diabetic mice”. Canadian Journal of Physiology and Pharmacology 74.5 (1996): 586-589.
  50. Meng K and Haberland GL. In: Haberland, Rohen JW, eds.Ki - ninogenases Kallikrein. F. K. Schattauer Verlag, Stuttgart, New York, (1973): 75-80.
  51. Campbell DJ., et al . “Increased tissue kallikrein levels in type 2 diabetes”. 53.4 (2010): 779-785.
  52. Sharma JN., et al . “Altered activities of kininsae II, an angio- tensin converting enzyme, prekallikrein and nitric oxide in Kuwaiti patients with type 2 diabetes”. International Journal of mmunopathology and Pharmacology (Italy) 28.2 (2015): 240-246
  53. Chao J., et al. “Tissue kallikrein elicites cardioprotection by direct kinin B2 receptor activation independent of kinin forma tion”. Hypertension 52.4 (2008): 715-720.
  54. Christopher J and Jaffa AA. “Diabetes modulates the expression of glomerular kinin receptors”. International Immunopharmacology 2 (2002): 1771-1779.

Copyright: © 2017 Jagdish N Sharma. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



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