Angiotensin II Type 1 Receptor Blockers Reduce Urinary Angiotensinogen Excretion and the Levels of Urinary Markers of Oxidative Stress and Inflammation in Patients with Type 2 Diabetic Nephropathy

Objective To demonstrate that the administration of an angiotensin (Ang) II type 1 receptor (AT1R) blocker (ARB) inhibits the vicious cycle of high glucose (HG)-reactive oxygen species (ROS)-angiotensinogen (AGT)-Ang II-AT1R-ROS by suppressing ROSs and inflammation, thus ameliorating diabetic nephropathy (DN). Research Design and Methods Thirteen hypertensive DN patients were administered ARBs, and the following parameters were evaluated before and 16 weeks after the treatment: urinary AGT (UAGT), albumin (albumin-creatinine ratio: ACR), 8-hydroxydeoxyguanosine (8-OHdG), 8-epi-prostaglandin F2α (8-epi-PGF2α), monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, and IL-10. Results ARB treatment reduced the blood pressure and urinary levels of AGT, ACR, 8-OHdG, 8-epi-PGF2α, MCP-1, and IL-6 but increased the urinary levels of IL-10. The reduction rate of UAGT correlated with the reduction rate of blood pressure; the reduction rates of the urinary ACR, 8-OHdG, 8-epi-PGF2α, MCP-1, and IL-6 levels; and the increase rate of the urinary IL-10 levels. Moreover, subjects who had high UAGT values at baseline exhibited higher reduction rates of urinary albumin excretion. Conclusions ARB-induced blockade of the abovementioned vicious cycle contributes to the renoprotective effects of ARBs in DN. The urinary levels of AGT could represent a predictive factor for reduced ACR in patients receiving ARB treatment.

[1]  H. Kobori,et al.  Urinary Angiotensinogen as a Novel Biomarker of the Intrarenal Renin-Angiotensin System Status in Hypertensive Patients , 2009, Hypertension.

[2]  H. Kobori,et al.  Urinary angiotensinogen as a potential biomarker of severity of chronic kidney diseases. , 2008, Journal of the American Society of Hypertension : JASH.

[3]  Fang Liu,et al.  Attenuation of Interstitial Fibrosis and Tubular Apoptosis in db/db Transgenic Mice Overexpressing Catalase in Renal Proximal Tubular Cells , 2008, Diabetes.

[4]  H. Kobori,et al.  Novel sandwich ELISA for human angiotensinogen. , 2007, American journal of physiology. Renal physiology.

[5]  J. S. Kim,et al.  Activation of the renin-angiotensin system within podocytes in diabetes. , 2007, Kidney international.

[6]  J. Ingelfinger,et al.  Catalase overexpression attenuates angiotensinogen expression and apoptosis in diabetic mice. , 2007, Kidney international.

[7]  S. Ito,et al.  Angiotensin II Type 1 Receptor Blockers Reduce Urinary Oxidative Stress Markers in Hypertensive Diabetic Nephropathy , 2006, Hypertension.

[8]  Ashutosh Kumar Singh,et al.  A novel mechanism for angiotensin II formation in streptozotocin-diabetic rat glomeruli. , 2005, American journal of physiology. Renal physiology.

[9]  G. Wolf.  New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology , 2004, European journal of clinical investigation.

[10]  D. Casarini,et al.  High glucose concentration stimulates intracellular renin activity and angiotensin II generation in rat mesangial cells. , 2004, American journal of physiology. Renal physiology.

[11]  I. G. Fantus,et al.  High glucose stimulates angiotensinogen gene expression and cell hypertrophy via activation of the hexosamine biosynthesis pathway in rat kidney proximal tubular cells. , 2003, Endocrinology.

[12]  J. Ingelfinger,et al.  High glucose stimulates angiotensinogen gene expression via reactive oxygen species generation in rat kidney proximal tubular cells. , 2002, Endocrinology.

[13]  J. Ingelfinger,et al.  High levels of glucose stimulate angiotensinogen gene expression via the P38 mitogen-activated protein kinase pathway in rat kidney proximal tubular cells. , 2000, Endocrinology.

[14]  K. Nath,et al.  Angiotensin II induces renal oxidant stress in vivo and heme oxygenase-1 in vivo and in vitro. , 2000, Kidney international.