Tyrosine kinase inhibitor, genistein, reduces renal inflammation and injury in streptozotocin-induced diabetic mice

Ahmed Abdelrazik Elmarakby, Ahmed Salah Ibrahim, Jessica Faulkner, Mahmood S Mozaffari, Gregory I Liou, Rafik A Abdelsayed

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Tyrosine kinase inhibition is known to reduce diabetes-induced end-organ damage but the mechanisms remain elusive. We hypothesized that inhibition of tyrosine kinase reduces renal inflammation and injury in streptozotocin-induced diabetes. Male C57BL/6 mice were given daily injections of streptozotocin (45. mg/kg/day, i.p. for 5. days); control animals received the vehicle (citrate buffer). Thereafter, streptozotocin-treated mice were treated with genistein (10. mg/kg, i.p three times a week for 10. weeks, n = 8-10/group) or the vehicle (5% DMSO). The streptozotocin-treated mice displayed significant elevation in blood glucose level and decrease in plasma insulin level compared to their vehicle-treated controls. Treatment with genistein reduced blood glucose level (~. 15%; p. <. 0.05) without a significant effect on plasma insulin level; however, blood glucose remained significantly higher than the control group. The development of diabetes was associated with significant increases in total protein, albumin, nephrin and collagen excretions compared to their controls. In addition, the diabetic mice displayed increased urinary MCP-1 excretion in association with increased renal ICAM-1 expression and apoptotic cells. Furthermore, renal gp91 expression levels and urinary Thio-Barbituric Acid Reactive Substances (TBARs) excretion, indices of oxidative stress, were also elevated in diabetic mice. These changes were associated with increased renal phospho-tyrosine expression and renal phospho-ERK/ERK ratio. Importantly, treatment with genistein reduced all these parameters towards control values. Collectively, the results suggest that the reno-protective effect of genistein likely relates to reduced renal inflammation, oxidative stress and apoptosis in diabetic mice.

Original languageEnglish (US)
Pages (from-to)149-156
Number of pages8
JournalVascular Pharmacology
Volume55
Issue number5-6
DOIs
StatePublished - Nov 1 2011

Fingerprint

Genistein
Streptozocin
Protein-Tyrosine Kinases
Inflammation
Kidney
Wounds and Injuries
Blood Glucose
Oxidative Stress
Insulin
Experimental Diabetes Mellitus
Intercellular Adhesion Molecule-1
Dimethyl Sulfoxide
Inbred C57BL Mouse
Citric Acid
Tyrosine
Albumins
Buffers
Collagen
Apoptosis
Control Groups

Keywords

  • Albuminuria
  • Diabetes
  • Gp91phox
  • ICAM-1
  • Nephrinuria
  • P-tyrosine

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

Cite this

Tyrosine kinase inhibitor, genistein, reduces renal inflammation and injury in streptozotocin-induced diabetic mice. / Elmarakby, Ahmed Abdelrazik; Ibrahim, Ahmed Salah; Faulkner, Jessica; Mozaffari, Mahmood S; Liou, Gregory I; Abdelsayed, Rafik A.

In: Vascular Pharmacology, Vol. 55, No. 5-6, 01.11.2011, p. 149-156.

Research output: Contribution to journalArticle

@article{c5e395e7169a4172a6bc3eb2e76483da,
title = "Tyrosine kinase inhibitor, genistein, reduces renal inflammation and injury in streptozotocin-induced diabetic mice",
abstract = "Tyrosine kinase inhibition is known to reduce diabetes-induced end-organ damage but the mechanisms remain elusive. We hypothesized that inhibition of tyrosine kinase reduces renal inflammation and injury in streptozotocin-induced diabetes. Male C57BL/6 mice were given daily injections of streptozotocin (45. mg/kg/day, i.p. for 5. days); control animals received the vehicle (citrate buffer). Thereafter, streptozotocin-treated mice were treated with genistein (10. mg/kg, i.p three times a week for 10. weeks, n = 8-10/group) or the vehicle (5{\%} DMSO). The streptozotocin-treated mice displayed significant elevation in blood glucose level and decrease in plasma insulin level compared to their vehicle-treated controls. Treatment with genistein reduced blood glucose level (~. 15{\%}; p. <. 0.05) without a significant effect on plasma insulin level; however, blood glucose remained significantly higher than the control group. The development of diabetes was associated with significant increases in total protein, albumin, nephrin and collagen excretions compared to their controls. In addition, the diabetic mice displayed increased urinary MCP-1 excretion in association with increased renal ICAM-1 expression and apoptotic cells. Furthermore, renal gp91 expression levels and urinary Thio-Barbituric Acid Reactive Substances (TBARs) excretion, indices of oxidative stress, were also elevated in diabetic mice. These changes were associated with increased renal phospho-tyrosine expression and renal phospho-ERK/ERK ratio. Importantly, treatment with genistein reduced all these parameters towards control values. Collectively, the results suggest that the reno-protective effect of genistein likely relates to reduced renal inflammation, oxidative stress and apoptosis in diabetic mice.",
keywords = "Albuminuria, Diabetes, Gp91phox, ICAM-1, Nephrinuria, P-tyrosine",
author = "Elmarakby, {Ahmed Abdelrazik} and Ibrahim, {Ahmed Salah} and Jessica Faulkner and Mozaffari, {Mahmood S} and Liou, {Gregory I} and Abdelsayed, {Rafik A}",
year = "2011",
month = "11",
day = "1",
doi = "10.1016/j.vph.2011.07.007",
language = "English (US)",
volume = "55",
pages = "149--156",
journal = "Vascular Pharmacology",
issn = "1537-1891",
publisher = "Elsevier Inc.",
number = "5-6",

}

TY - JOUR

T1 - Tyrosine kinase inhibitor, genistein, reduces renal inflammation and injury in streptozotocin-induced diabetic mice

AU - Elmarakby, Ahmed Abdelrazik

AU - Ibrahim, Ahmed Salah

AU - Faulkner, Jessica

AU - Mozaffari, Mahmood S

AU - Liou, Gregory I

AU - Abdelsayed, Rafik A

PY - 2011/11/1

Y1 - 2011/11/1

N2 - Tyrosine kinase inhibition is known to reduce diabetes-induced end-organ damage but the mechanisms remain elusive. We hypothesized that inhibition of tyrosine kinase reduces renal inflammation and injury in streptozotocin-induced diabetes. Male C57BL/6 mice were given daily injections of streptozotocin (45. mg/kg/day, i.p. for 5. days); control animals received the vehicle (citrate buffer). Thereafter, streptozotocin-treated mice were treated with genistein (10. mg/kg, i.p three times a week for 10. weeks, n = 8-10/group) or the vehicle (5% DMSO). The streptozotocin-treated mice displayed significant elevation in blood glucose level and decrease in plasma insulin level compared to their vehicle-treated controls. Treatment with genistein reduced blood glucose level (~. 15%; p. <. 0.05) without a significant effect on plasma insulin level; however, blood glucose remained significantly higher than the control group. The development of diabetes was associated with significant increases in total protein, albumin, nephrin and collagen excretions compared to their controls. In addition, the diabetic mice displayed increased urinary MCP-1 excretion in association with increased renal ICAM-1 expression and apoptotic cells. Furthermore, renal gp91 expression levels and urinary Thio-Barbituric Acid Reactive Substances (TBARs) excretion, indices of oxidative stress, were also elevated in diabetic mice. These changes were associated with increased renal phospho-tyrosine expression and renal phospho-ERK/ERK ratio. Importantly, treatment with genistein reduced all these parameters towards control values. Collectively, the results suggest that the reno-protective effect of genistein likely relates to reduced renal inflammation, oxidative stress and apoptosis in diabetic mice.

AB - Tyrosine kinase inhibition is known to reduce diabetes-induced end-organ damage but the mechanisms remain elusive. We hypothesized that inhibition of tyrosine kinase reduces renal inflammation and injury in streptozotocin-induced diabetes. Male C57BL/6 mice were given daily injections of streptozotocin (45. mg/kg/day, i.p. for 5. days); control animals received the vehicle (citrate buffer). Thereafter, streptozotocin-treated mice were treated with genistein (10. mg/kg, i.p three times a week for 10. weeks, n = 8-10/group) or the vehicle (5% DMSO). The streptozotocin-treated mice displayed significant elevation in blood glucose level and decrease in plasma insulin level compared to their vehicle-treated controls. Treatment with genistein reduced blood glucose level (~. 15%; p. <. 0.05) without a significant effect on plasma insulin level; however, blood glucose remained significantly higher than the control group. The development of diabetes was associated with significant increases in total protein, albumin, nephrin and collagen excretions compared to their controls. In addition, the diabetic mice displayed increased urinary MCP-1 excretion in association with increased renal ICAM-1 expression and apoptotic cells. Furthermore, renal gp91 expression levels and urinary Thio-Barbituric Acid Reactive Substances (TBARs) excretion, indices of oxidative stress, were also elevated in diabetic mice. These changes were associated with increased renal phospho-tyrosine expression and renal phospho-ERK/ERK ratio. Importantly, treatment with genistein reduced all these parameters towards control values. Collectively, the results suggest that the reno-protective effect of genistein likely relates to reduced renal inflammation, oxidative stress and apoptosis in diabetic mice.

KW - Albuminuria

KW - Diabetes

KW - Gp91phox

KW - ICAM-1

KW - Nephrinuria

KW - P-tyrosine

UR - http://www.scopus.com/inward/record.url?scp=84866556074&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866556074&partnerID=8YFLogxK

U2 - 10.1016/j.vph.2011.07.007

DO - 10.1016/j.vph.2011.07.007

M3 - Article

C2 - 21807121

AN - SCOPUS:84866556074

VL - 55

SP - 149

EP - 156

JO - Vascular Pharmacology

JF - Vascular Pharmacology

SN - 1537-1891

IS - 5-6

ER -