Skip to main content
Log in

Garlic (Allium sativum) down-regulates the expression of angiotensin II AT1 receptor in adrenal and renal tissues of streptozotocin-induced diabetic rats

  • Research Article
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

The up-regulation of angiotensin II AT1 receptors has been implicated as a major mediator in the development of hypertension and progressive nephropathy in experimental diabetes. In spite of the documented potential of garlic treatments in ameliorating diabetic complications, the possible involvement of the angiotensin II AT1 receptor, as a central target for the anti-diabetic potential of garlic, has not been explored. Three groups of rats were studied after 8 weeks following diabetes induction: normal, streptozotocin-induced diabetic (control diabetic), and garlic-treated diabetic rats. A polyclonal antibody of proven specificity to the AT1 receptor, as verified by western blotting, indicated in immunohistochemical assays that AT1 receptor labeling was significantly increased in adrenal and renal tissues of control diabetic rats compared to the normal group. The increased AT1 receptor labeling involved all cortical zones and medullary chromaffin cells of the adrenal gland. Except for glomerulii, increased AT1 receptor labeling was also evident in proximal convoluted tubules in the renal cortex, and all tubular segments and interstitial cells outlining the vasa recta bundles in the inner stripe of the outer renal medulla. Compared with control diabetic rats, the labeling of the AT1 receptor in the garlic-treated diabetic group was significantly reduced throughout adrenal and renal regions to levels comparable to those observed in normal rats. The capacity of garlic to modulate diabetes-induced AT1 receptor up-regulation may be implicated in reversing the detrimental consequences of excessive Ang II signaling, manifested by the development of hypertension and nephropathy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Ahmad MS, Ahmed N (2006) Antiglycation properties of aged garlic extract: possible role in prevention of diabetic complication. J Nutr 136:796S–799S

    CAS  PubMed  Google Scholar 

  • Ahmad MS, Pischetsrieder M, Ahmed N (2007) Aged garlic extract and S-allyl cysteine prevents formation of advanced glycation endproducts. Eur J Pharmacol 561(1–3):32–38

    Article  CAS  PubMed  Google Scholar 

  • Al-Qattan K, Al-Akhawand S, Mansour MH (2006) Immunohistochemical localization of distinct angiotensin II AT1 receptor isoforms in the kidneys of the Sprague-Dawley rat and the desert rodent Meriones crassus. Anat Histol Embryol 35:130–138

    Article  CAS  PubMed  Google Scholar 

  • Al-Qattan K, Thomson M, Ali M (2008) Garlic (Allium sativum) and ginger (Zingiber officinale) attenuate structural nephropathy progression in streptozotocin-induced diabetic rats. e-SPN. doi:10.1016/j.eclnm

  • Amagase H (2006) Clarifying the real bioactive constituents of garlic. J Nutr 136:716S–725S

    CAS  PubMed  Google Scholar 

  • Atlas SA (2007) The renin-angiotensin aldosterone system: patho-physiological role and pharmacologic inhibition. J Manag Care Pharm 13(8):S9–S20

    Google Scholar 

  • Banday AA, Lokhandwala MF (2008) Oxidative stress-induced renal angiotensin AT1 receptor upregulation causes increased stimulation of sodium transporters and hypertension. Am J Physiol Renal Physiol 295:F698–F706

    Article  CAS  PubMed  Google Scholar 

  • Becker M, Umrani D, Lokhandwala MF, Hussain T (2003) Increased renal angiotensin II AT1 receptor function in obese Zucker rat. Clin Exp Hypertens 25:35–47

    Article  CAS  PubMed  Google Scholar 

  • Brenner BM, Cooper ME, de Zeeuw D et al (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes mellitus and nephropathy. N Engl J Med 345:861–869

    Article  CAS  PubMed  Google Scholar 

  • Brewster UC, Perazella MA (2004) The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease. Am J Med 116(4):263–272

    Article  CAS  PubMed  Google Scholar 

  • Brown L, Wall D, Marchant C, Sernia C (1997) Tissue-specific changes in angiotensin II receptors in streptozotocin-diabetic rats. J Endocrinol 154(2):355–362

    Article  CAS  PubMed  Google Scholar 

  • Burns KD (2000) Angiotensin II and its receptors in the diabetic kidney. Am J Kidney Dis 36(3):449–467

    CAS  PubMed  Google Scholar 

  • Drobiova H, Thomson M, Al-Qattan K et al (2009) Garlic increases antioxidant levels in diabetic and hypertensive rats determined by a modified peroxidase method. eCAM. doi:10.1093/ecam/nep011

  • Giles EM, Fernley RT, Nakamura Y et al (1999) Characterization of a specific antibody to the rat angiotensin II AT1 receptor. J Histochem Cytochem 47:507–515

    Article  CAS  PubMed  Google Scholar 

  • Gnudi L, Goldsmith D (2010) Renin angiotensin aldosterone system (RAAS) inhibitors in the prevention of early renal disease in diabetes. Med Rep 2(18):1–4

    Google Scholar 

  • Higuchi S, Ohtsu H, Suzuki H et al (2007) Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology. Clin Sci (Lond) 112:417–428

    Article  CAS  Google Scholar 

  • Hosseini M, Shafiee SM, Baluchnejadmojarad T (2007) Garlic extract reduces serum angiotensin converting enzyme (ACE) activity in nondiabetic and streptozotocin-diabetic rats. Pathophysiology 14(2):109–112

    Article  CAS  PubMed  Google Scholar 

  • Jayadev S, Smith RD, Jagadeesh G, Baukal AJ, Hunyady L, Catt KJ (1999) N-linked glycosylation is required for optimal AT1a angiotensin receptor expression in COS-7 cells. Endocrinology 140:2010–2017

    Article  CAS  PubMed  Google Scholar 

  • Kagami S, Border WA, Miller DE, Noble NA (1994) Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest 93:2431–2437

    Article  CAS  PubMed  Google Scholar 

  • Kalinyak JE, Sechi LA, Griffin CA et al (1993) The rennin angiotensin system in streptozotocin-induced diabetes mellitus in the rat. J Am Soc Nephrol 4:1337–1345

    CAS  PubMed  Google Scholar 

  • Kaschina E, Unger T (2003) Angiotensin AT1/AT2 receptors: regulation, signaling and function. Blood Press 12:70–88

    Article  CAS  PubMed  Google Scholar 

  • Kasuga S, Ushijima M, Morihara N et al (1999) Effect of aged garlic extract (AGE) on hyperglycemia induced by immobilization stress in mice. Nippon Yakurigaku Zasshi 114(3):191–197

    Article  CAS  PubMed  Google Scholar 

  • Kennefick TM, Oyama TT, Thompson MM et al (1996) Enhanced renal sensitivity to angiotensin actions in diabetes mellitus in the rat. Am J Physiol 271:595–602

    Google Scholar 

  • Kobori H, Nangaku M, Navar LG, Nishiyama A (2007) The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 59:251–287

    Article  CAS  PubMed  Google Scholar 

  • Laemmli UK (1970) Cleavage of structural protein during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  CAS  PubMed  Google Scholar 

  • Lanctôt PM, Leclerc PC, Clemente M, Auger-Messier M, Escher E, Leduc R, Guillemette G (2005) Importance of N-glycosylation positioning for cell-surface expression, targeting, affinity and quality control of the human AT1 receptor. Biochem J 390:367–376

    Article  PubMed  Google Scholar 

  • Lanctôt PM, Leclerc PC, Escher E, Guillemette G, Leduc R (2006) Role of N-glycan-dependent quality control in the cell-surface expression of the AT1 receptor. Biochem Biophys Res Commun 340(2):395–402

    Article  PubMed  Google Scholar 

  • Lewis EJ, Hunsicker LG, Clarke WR et al (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860

    Article  CAS  PubMed  Google Scholar 

  • Liu CT, Sheen LY, Lii CK (2007) Does garlic have a role as an anti-diabetic agent? Mol Nutr Food Res 51(11):1353–1364

    Article  CAS  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • Murphy TJ, Alexander RW, Griendling KK et al (1991) Isolation of a cDNA encoding the vascular type 1 angiotensin II receptor. Nature 351:233–236

    Article  CAS  PubMed  Google Scholar 

  • Navar LG, Nishiyama A (2004) Why are angiotensin concentrations so high in the kidney? Curr Opin Nephrol Hypertens 13:107–115

    Article  CAS  PubMed  Google Scholar 

  • Palumbo PJ (2001) Glycemic control, mealtime glucose excursions, and diabetic complications in type 2 diabetes mellitus. Mayo Clin Proc 76:609–618

    CAS  PubMed  Google Scholar 

  • Parving HH, Lehnert H, Brochner-Mortensen J et al (2001) Irbesartan in patients with type 2 diabetes and microalbuminuria study group: the effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870–878

    Article  CAS  PubMed  Google Scholar 

  • Paul M, Poyan Mehr A, Kreutz R (2006) Physiology of local renin-angiotensin systems. Physiol Rev 86:747–803

    Article  CAS  PubMed  Google Scholar 

  • Pavel J, Benicky J, Larrayoz-Roland I et al (2008) Peripherally administered Angiotensin II AT1 receptor antagonists are anti-stress compounds in vivo. Ann N Y Acad Sci 1148:360–366

    Article  CAS  PubMed  Google Scholar 

  • Pedraza-Chaverrí J, Barrera D, Maldonado PD et al (2004) S-allylmercaptocysteine scavenges hydroxyl radical and singlet oxygen in vitro and attenuates gentamicin-induced oxidative and nitrosative stress and renal damage in vivo. BMC Clin Pharmacol 4:5–18

    Article  PubMed  Google Scholar 

  • Quan A, Baum M (1998) Endogenous angiotensin II modulates rat proximal tubule transport with acute changes in extracellular volume. Am J Physiol Renal Physiol 275:F74–F78

    CAS  Google Scholar 

  • Rábano M, Peña A, Brizuela L et al (2004) Angiotensin II-stimulated cortisol secretion is mediated by phospholipase D. Mol Cell Endocrinol 222(1–2):9–20

    Article  PubMed  Google Scholar 

  • Reja V, Goodchild AK, Phillips JK, Pilowsky PM (2006) Upregulation of angiotensin AT1 receptor and intracellular kinase gene expression in hypertensive rats. Clin Exp Pharmacol Physiol 33:690–695

    Article  CAS  PubMed  Google Scholar 

  • Roberge C, Carpentier AC, Langlois M-F et al (2007) Adrenocortical dysregulation as a major player in insulin resistance and onset of obesity. Am J Physiol Endocrinol Metab 293:E1465–E1478

    Article  CAS  PubMed  Google Scholar 

  • Shah S, Hussain T (2006) Enhanced angiotensin II-induced activation of Na+, K+-ATPase in the proximal tubules of obese Zucker rats. Clin Exp Hypertens 28:29–40

    Article  CAS  PubMed  Google Scholar 

  • Sharma K, Jin Y, Cuo J, Ziyadeh FN (1996) Neutralization of TGF-β by anti-TGF-β antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes 45:522–530

    Article  CAS  PubMed  Google Scholar 

  • Siragy HM (2004) AT1 and AT2 receptor in the kidney: role in health and disease. Semin Nephrol 24:93–100

    Article  CAS  PubMed  Google Scholar 

  • Siragy HM, Awad AA, Abadir PM, Webb R (2003) The angiotensin II type 1 receptor mediates renal interstitial content of tumor necrosis factor-α in diabetic rats. Endocrinology 144:2229–2233

    Article  CAS  PubMed  Google Scholar 

  • Thaiss F, Wolf G, Assad N, Zahner G, Stahl RA (1996) Angiotensinase A gene expression and enzyme activity in isolated glomeruli of diabetic rats. Diabetologia 39:275–280

    Article  CAS  PubMed  Google Scholar 

  • Thomson M, Al-Amin ZM, Al-Qattan KK et al (2007) Anti-diabetic and hypolipidaemic properties of garlic (Allium sativum) in streptozotocin-induced diabetic rats. Int J Diabetes Metab 15(108–115):42

    Google Scholar 

  • Vazquez-Prieto MA, González RE, Renna NF et al (2010) Aqueous garlic extracts prevent oxidative stress and vascular remodeling in an experimental model of metabolic syndrome. J Agric Food Chem 58(11):6630–6635

    Article  CAS  PubMed  Google Scholar 

  • Villa E, Rabano A, Cazes M et al (1997) Effects of UP269-6, a new angiotensin II receptor antagonist, and captopril on the progression of rat diabetic nephropathy. Am J Hypertens 10:275–281

    Article  CAS  PubMed  Google Scholar 

  • Wehbi GJ, Zimpelmann J, Carey RM et al (2001) Early streptozotocin-diabetes mellitus downregulates rat kidney AT2 receptors. Am J Physiol Renal Physiol 280:F254–F265

    CAS  PubMed  Google Scholar 

  • Weir MR (2007) Effects of rennin–angiotensin system inhibition on end-organ protection: can we do better? Clin Ther 29(9):1803–1824

    Article  CAS  PubMed  Google Scholar 

  • Weir MR, Dzau VJ (1999) The renin–angiotensin–aldosterone system: a specific target for hypertension management. Am J Hypertens 12:205S–213S

    Article  CAS  PubMed  Google Scholar 

  • Wolf G (1998) Molecular mechanisms of angiotensin II in the kidney: emerging role in the progression of renal disease: beyond haemodynamics. Nephrol Dial Transplant 13:1131–1142

    Article  CAS  PubMed  Google Scholar 

  • Wolf G, Mueller E, Stahl RAK, Ziyadeh FN (1993) Angiotensin II-induced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factor-β. J Clin Invest 92:1366–1372

    Article  CAS  PubMed  Google Scholar 

  • Wolf G, Sharma K, Chen Y et al (1992) High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-β. Kidney Int 41(369–402):19

    Google Scholar 

  • Wolf G, Ziyadeh FN, Stahl RA (1999) Angiotensin II stimulates expression of transforming growth factor beta receptor type II in cultured mouse proximal tubular cells. J Mol Med 77:556–564

    Article  CAS  PubMed  Google Scholar 

  • Xue C, Siragy HM (2005) Local renal aldosterone system and its regulation by salt, diabetes, and angiotensin II Type 1 receptor. Hypertension 46:584–590

    Article  CAS  PubMed  Google Scholar 

  • Younis F, Mirelman D, Rabinkov A, Rosenthal T (2010) S-allyl-mercapto-captopril: a novel compound in the treatment of Cohen-Rosenthal diabetic hypertensive rats. J Clin Hypertens 12(6):451–455

    Article  CAS  Google Scholar 

  • Zhuo J, MacGregor DP, Mendelsohn FAO (1996) Comparative distribution of angiotensin II receptor subtypes in mammalian adrenal glands. In: Vinson GP, Anderson DC (eds) Adrenal glands, vascular system and hypertension. Journal of Endocrinology Ltd, Bristol, pp 53–68

    Google Scholar 

  • Zhuo J, Maric C, Harris PJ et al (1997) Localization and functional properties of angiotensin II AT1 receptors in the kidney: focus on renomedullary interstitial cells. Hypertens Res 20:233–250

    Article  CAS  PubMed  Google Scholar 

  • Ziyadeh FN, Sharma K, Ericksen M, Wolf G (1994) Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose in mediated by activation of transforming growth factor-β. J Clin Invest 93:536–542

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Supported by Research Project # 2007-1302-04 funded by Kuwait Foundation for the Advancement of Science and Research Projects # SL 06/08 and 09/10, funded by Kuwait University.

Conflict of interest

The authors are not employees or consultants associated with any commercial company, and there were no conflicts of interest in the present study.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mohamed H. Mansour.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mansour, M.H., Al-Qattan, K., Thomson, M. et al. Garlic (Allium sativum) down-regulates the expression of angiotensin II AT1 receptor in adrenal and renal tissues of streptozotocin-induced diabetic rats. Inflammopharmacol 21, 147–159 (2013). https://doi.org/10.1007/s10787-012-0139-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-012-0139-3

Keywords

Navigation