Inhibition of Rac 1 Protect Against Platelet Induced Liver and Kidney ‎Injury in Diabetes Mellitus

Keywords: Rac1‎, Platelet, CXCL4‎, Diabetes Mellitus, Liver and Kidney Injury ‎


Diabetes mellitus both (Type 1 and Type 2) are one of the common causes for activation of platelet. Inflammation-induced abnormal platelet function contributes to chronic complications, which are the leading causes of death and morbidity among diabetics. Rac1 has been shown to regulate a variety of platelet functions; predicted Rac1could regulate platelet release of CXCL4, which leads to kidney injury in Diabetes Mellitus. Diabetes mellitus' effect on Rac1 activation, a 21kD G-protein implicated in platelet activation, was investigated and platelet induced inflammation and kidney injury. Swiss albino male mice were pretreated with 5 mg/kg of a specific Rac1 inhibitor NSC23766 and injected with (45 mg/kg body wt.) streptozotocin, twice for five days. Moreover, the concentration of serum chemokines CXCL4 were assayed using ELISA and histology score for kidney were examined. Our results showed that Diabetes mellitus was induced in mice by streptozotocin. In addition, platelet chemokines (CXCL4) were markedly higher in diabetic mice when compared to the sham (control) group. Moreover, pretreatment with NSC23766 decreased liver and kidney injury assessed by histology score, P-value <0.05. Our study reveals that Rac1 has a critical role in platelet chemokines secretion due to diabetes-induced inflammation in the liver and kidneys, targeting Rac1 could be a target for innovative treatment to control inflammation in diabetic individual. Targeting platelets involved in inflammatory pathways could be part of a strategy in order to control and manage diabetes and its consequences.


Download data is not yet available.

Author Biographies

Rundk A. Hwaiz, Department of Clinical Biochemistry, Hawler Medical University, Kurdistan Region, Iraq

Dr. Rundk Ahmad Hwaiz is Assistant professor in Medical Biochemistry at Hawler Medical University. She is Head of Nutrition and Dietetics Department in College of Health Sciences- Hawler Medical University. In 2015 she finished her PhD degree in Medical Sciences at Surgery Section-College of Medicine-Lund University-Sweden. She did post doctorate at Malmo University in 2017-2019 in prostate and skin cancer. Her research interest is sepsis, pancreatitis, ketogenic diet, metabolic syndrome, COVID-19, and cancer. She has collaborated actively with researchers in several other disciplines of biomedicine on finding molecular mechanisms of the metabolic and inflammatory disease.

Helen J. Sabri, Department of Medical Biochemical Analysis, Cihan University-Erbil, Kurdistan Region, Iraq

Helen Jawdat Sabri is an assistant lecturer (Full) in Medical Biochemical Analysis at Cihan University. In 2022 she finished MSc in clinical Biochemistry at Hawler Medical University, College of health sciences. Her research interest is Clinical Biochemistry, Diabetes, and cancer.


D. L. Eizirik, L. Pasquali and M. Cnop. Pancreatic β-cells in Type 1 and Type 2 diabetes mellitus: Different pathways to failure. Nature Reviews Endocrinology, vol. 16, no. 7, pp. 349-362, 2020.

D. Atlas. IDF Diabetes Atlas. 7th ed. International Diabetes Federation, Brussels, Belgium, 2015.

V. Chaurasia, S. Pal and B. Tiwari. Chronic kidney disease: A predictive model using decision tree. International Journal of Engineering Research and Technology, vol. 11, pp. 1781-1794, 2018.

A. Misra, N. Tandon, S. Ebrahim, N. Sattar, D. Alam, U. Shrivastava, K. M. V. Narayan and T. H. Jafar. Diabetes, cardiovascular disease and chronic kidney disease in South Asia: Current status and future directions. BMJ, vol. 357, p. j1420, 2017.

B. M. Brenner, T. H. Hostetter, J. L. Olson, H. G. Rennke and M. A. Venkatachalam. The role of glomerular hyperfiltration in the initiation and progression of diabetic nephropathy. Acta Endocrinologica (Copenhagen), vol. 242, pp. 7-10, 1981.

T. H. Hostetter, J. L. Troy and B. M. Brenner. Glomerular hemodynamics in experimental diabetes mellitus. Kidney International, vol. 19, no. 3, pp. 410-415, 1981.

T. Shibabaw, G. Dessie, M. D. Molla, M. F. Zerihun and B. Ayelign. Assessment of liver marker enzymes and its association with Type 2 diabetes mellitus in Northwest Ethiopia. BMC Research Notes, vol. 12, no. 1, pp. 1-5, 2019.

S. H. Alzahrani, M. Baig, J. I. Bashawri, M. M. Aashi, F. K. Shaibi and D. A. Alqarni. Prevalence and association of elevated liver transaminases in Type 2 diabetes mellitus patients in Jeddah, Saudi Arabia. Cureus, vol. 11, no. 7, p. e5166, 2019.

T. A. Kodiatte, U. K. Manikyam, S. B. Rao, T. M. Jagadish, M. Reddy, H. K. Lingaiah and V. Lakshmaiah. Mean platelet volume in Type 2 diabetes mellitus. Journal of Laboratory Physicians, vol. 4, no. 01, p. 5-9, 2012.

R. A. Hwaiz. Rac 1 Project against Diabetes Mellitus via Attenuation of Platelet Chemokines. Hawler Medical University, Iraq, p. 81, 2019.

P. Balakumar, K. Maung-U and G. Jagadeesh. Prevalence and prevention of cardiovascular disease and diabetes mellitus. Pharmacological Research, vol. 113, pp. 600-609, 2016.

D. Cosentino-Gomes, N. Rocco-Machado and J. R. Meyer- Fernandes. Cell signaling through protein kinase C oxidation and activation. International Journal of Molecular Sciences, vol. 13, no. 9, pp. 10697-10721, 2012.

R. Hwaiz, M. Rahman, E. Zhang and H. Thorlacius. Platelet secretion of CXCL4 is Rac1‐dependent and regulates neutrophil infiltration and tissue damage in septic lung damage. British Journal of Pharmacology, vol. 172, no. 22, pp. 5347-5359, 2015.

R. Hwaiz, M. Rahman, I. Syk, E. Zhang and H. Thorlacius. Rac1-dependent secretion of platelet-derived CCL5 regulates neutrophil recruitment via activation of alveolar macrophages in septic lung injury. Journal of Leukocyte Biology, vol. 97, no. 5, pp. 975-984, 2015.

A. Abo, E. Pick, A. Hall, N. Totty, C. G. Teahan and A. W. Segal. Activation of the NADPH oxidase involves the small GTP-bindingprotein p21 rac1. Nature, vol. 353, no. 6345, pp. 668-670, 1991.

D. Diekmann, A. Abo, C. Johnston, A. W. Segal and A. Hall. Interaction of Rac with p67phox and regulation of phagocytic NADPH oxidase activity. Science, vol. 265, no. 5171, pp. 531-533, 1994.

B. T. Kinsella, R. A. Erdman and W. A. Maltese. Carboxyl-terminal isoprenylation of ras-related GTP-binding proteins encoded by rac1, rac2 and ralA. Journal of Biological Chemistry, vol. 266, no. 15, pp. 9786-9794, 1991.

G. G. Schiattarella, A. Carrizzo, F. Ilardi, A. Damato, M. Ambrosio, M. Madonna, V. Trimarco, M. Marino, E. De Angelis, S. Settembrini, C. Perrino, B. Trimarco, G. Esposito and C. Vecchione. Rac1 modulates endothelial function and platelet aggregation in diabetes mellitus. Journal of the American Heart Association, vol. 7, no. 8, p. e007322, 2018.

R. Hwaiz, M. Rahman, E. Zhang and H. Thorlacius. Rac1 regulates platelet shedding of CD40L in abdominal sepsis. Laboratory Investigation, vol. 94, no. 9, pp. 1054-1063, 2014.

B. L. Furman. Streptozotocin‐induced diabetic models in mice and rats. Current Protocols in Pharmacology, vol. 70, no. 1, pp. 5-47, 2015.

M. G. Binker, A. A. Binker-Cosen, H. Y. Gaisano and L. I. Cosen- Binker. Inhibition of Rac1 decreases the severity of pancreatitis and pancreatitis-associated lung injury in mice. Experimental Physiology, vol. 93, no. 10, pp. 1091-1103, 2008.

R. Hwaiz, Z. Hasan, M. Rahman, S. Zhang, K. Palani, I. Syk, B. Jeppsson and H. Thorlacius. Rac1 signaling regulates sepsisinduced pathologic inflammation in the lung via attenuation of Mac-1 expression and CXC chemokine formation. Journal of Surgical Research, vol. 183, no. 2, pp. 798-807, 2013.

S. A. Siddiqui, M. M. Or Rashid, M. G. Uddin, F. N. Robel, M. S. Hossain, M. A. Haque and M. Jakaria. Biological efficacy of zinc oxide nanoparticles against diabetes: A preliminary study conducted in mice. Bioscience Reports, vol. 40, no. 4, p. BSR20193972, 2020.

K. E. Ibrahim, M. G. Al-Mutary, A. O. Bakhiet and H. A. Khan. Histopathology of the liver, kidney and spleen of mice exposed to gold nanoparticles. Molecules, vol. 23, no. 8, p. 1848, 2018.

Y. Wang, R. Hwaiz, L. Luo, O. Ö. Braun, E. Norström and H. Thorlacius. Rac1 regulates bacterial toxin-induced thrombin generation. Inflammation Research, vol. 65, no. 5, pp. 405-413, 2016.

A. Barbera, R. R. Gomis, N. Prats, J.E. Rodriguez-Gil, M. Domingo, R. Gomis and J.J. Guinovart. Tungstate is an effective antidiabetic agent in streptozotocin-induced diabetic rats: A long-term study. Diabetologia, vol. 44, no. 4, pp. 507-513, 2001.

M. Iwase, M. Kikuchi, K. Nunoi, M. Wakisaka, Y. Maki, S. Sadoshima and M. Fujishima. A new model of Type 2 (noninsulin-dependent) diabetes mellitus in spontaneously hypertensive rats: Diabetes induced by neonatal streptozotocin treatment. Diabetologia, vol. 29, no. 11, pp. 808-811, 1986.

F. Palm. Diabetes-Induced Alterations in Renal Microcirculation and Metabolism. Uppsala Universitet, Sweden, 2004.

N. Jain, A. L. Corken, A. Kumar, C. L. Davis, J. Ware and J. M. Arthur. Role of platelets in chronic kidney disease. Journal of the American Society of Nephrology, vol. 32, no. 7, pp. 1551-1558, 2021.

M. P. Jansen, S. Florquin and J. J. Roelofs. The role of platelets in acute kidney injury. Nature Reviews Nephrology, vol. 14, no. 7, pp. 457-471, 2018.

J. M. López-Novoa. Potential role of platelet activating factor in acute renal failure. Kidney International, vol. 55, no. 5, pp. 1672- 1682, 1999.

G. H. Neild and M. P. Gordge. Platelet-endothelial interactions in renal injury. In: Platelet-Vessel Wall Interactions. Springer, New York, pp. 121-153, 1988.

M. A. Talat, N. A. Khalifa, L. M. Kamel, E. M. Mohammed and H. Shehata. The role of mean platelet volume in pediatric chronic kidney disease. The Egyptian Journal of Hospital Medicine, vol. 80, no. 1, pp. 678-682, 2020.

F. N. Ziyadeh, B.B. Hoffman, D.C. Han, M.C. Iglesias-De la Cruz, S.C. Hong, M. Isono, S. Chen, T.A. McGowan and K. Sharma. Long-term prevention of renal insufficiency, excess matrix gene expression and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-β antibody in db/db diabetic mice. Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 14, pp. 8015-8020, 2000.

Y. Zhang, X. Tan, Y. Cao, X. An, J. Chen and L. Yang. Punicalagin protects against diabetic liver injury by upregulating mitophagy and antioxidant enzyme activities. Nutrients, vol. 14, no. 14, p. 2782, 2022.

G. Tell, C. Vascotto and C. Tiribelli. Alterations in the redox state and liver damage: Hints from the EASL Basic School of Hepatology. Journal of Hepatology, vol. 58, no. 2, pp. 365-374, 2013.

Z. Sha, Y. Yang, R. Liu, H. Bao, S. Song, J. Dong, M. Guo, Y. Zhao, H. Liu and G. Ding. Hepatic ischemia-reperfusion injury in mice was alleviated by Rac1 inhibition-more than just ROS-inhibition. Journal of Clinical and Translational Hepatology, vol. 10, no. 1, p. 42, 2022.

H. A. Khan, K. E. Ibrahim, A. Khan, S. H. Alrokayan and A. S. Alhomida. Immunostaining of proinflammatory cytokines in renal cortex and medulla of rats exposed to gold nanoparticles. Histology and Histopathology, vol. 32, no. 6, pp. 597-607, 2017.

H. A. Khan, K. E. Ibrahim, A. Khan, S. H. Alrokayan, A. S. Alhomida and Y.K. Lee. Comparative evaluation of immunohistochemistry and real-time PCR for measuring proinflammatory cytokines gene expression in livers of rats treated with gold nanoparticles. Experimental and Toxicologic Pathology, vol. 68, no. 7, pp. 381-390, 2016.

H. A. Khan, M. A. K. Abdelhalim, A. S. Alhomida and M. S. Al-Ayed. Effects of naked gold nanoparticles on proinflammatory cytokines mRNA expression in rat liver and kidney. BioMed Research International, vol. 2013, p. 590730, 2013.

A. Mankowska, J. Pollak and G. Sypniewska. Association of C-reactive protein and other markers of inflammation with risk of complications in diabetic subjects. EJIFCC, vol. 17, no. 1, p. 8, 2006.

P. Marques, A. Collado, S. Martinez-Hervas, E. Domingo, E. Benito, L. Piqueras, J. T. Real, J. F. Ascaso and M. J. Sanz. Systemic inflammation in metabolic syndrome: Increased platelet and leukocyte activation and key role of CX3CL1/CX3CR1 and CCL2/CCR2 axes in arterial platelet-proinflammatory monocyte adhesion. Journal of Clinical Medicine, vol. 8, no. 5, p. 708, 2019.

L. Yao, O. Herlea-Pana, J. Heuser-Baker, Y. Chen and J. Barlic- Dicen. Roles of the chemokine system in development of obesity, insulin resistance and cardiovascular disease. Journal of Immunology Research, vol. 2014, p. 181450, 2014.

H. Kaneto, N. Katakami, M. Matsuhisa and T. Matsuoka. Role of reactive oxygen species in the progression of Type 2 diabetes and atherosclerosis. Mediators of Inflammation, vol. 2010, p. 453892, 2010.

C. M. O. Volpe, P. H. Villar-Delfino, P. M. F. Dos Anjos and J. A. Nogueira-Machado. Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death and Disease, vol. 9, no. 2, pp. 1-9, 2018.

C. Henríquez-Olguin, J. R. Knudsen, S. H. Raun, Z. Li, E. Dalbram, J. T. Treebak, L. Sylow, R. Holmdahl, E. A. Richter, E. Jaimovich and T. E. Jensen. Cytosolic ROS production by NADPH oxidase 2 regulates muscle glucose uptake during exercise. Nature Communications, vol. 10, no. 1, pp. 1-11, 2019.

P. L. Hordijk. Regulation of NADPH oxidases: The role of Rac proteins. Circulation Research, vol. 98, no. 4, pp. 453-462, 2006.

How to Cite
Hwaiz R, Sabri H. Inhibition of Rac 1 Protect Against Platelet Induced Liver and Kidney ‎Injury in Diabetes Mellitus. cuesj [Internet]. 1Mar.2023 [cited 16Jun.2024];7(1):29-4. Available from:
Research Article