Original Report: Laboratory Investigation

High Ambient Glucose Augments Angiotensin II-Induced Proinflammatory Gene mRNA Expression in Human Mesangial Cells: Effects of Valsartan and Simvastatin
Masayo Naito^a, Ananth Shenoy^c, Isao Aoyama^a, Joseph S. Koopmeiners^b, Radko Komers^d, H. William Schnaper^e, Karol Bomsztyk<sup>a

a</sup>UW Medicine Lake Union Research, and
^bDepartment of Biostatistics, University of Washington, Seattle, Wash.,
^cNovartis Pharmaceuticals Corporation, and
^dDivision of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oreg., and
^eDepartment of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Ill., USA

Address of Corresponding Author

Am J Nephrol 2009;30:99-111 (DOI: 10.1159/000203619)

  Key Words

• Angiotensin II
• Hyperglycemia
• Glomerular mesangial cell
• Proinflammatory action

  Abstract

Background: Hyperglycemia may potentiate the adverse renal effects of angiotensin II (AII). In the kidney, the major target of AII action is the glomerular mesangial cell, where its hemodynamic and proinflammatory action contributes to renal injury. AII action is mediated by several types of cell receptors. Among those, the AT₁ receptor has been best studied using specific AII receptor blockers (ARBs). These agents have emerged as major new modalities in the prevention and amelioration of renal disease where the ARB renoprotective anti-inflammatory properties could be more important than previously appreciated. Like the ARBs, statins may also modulate inflammatory responses that are renoprotective and complement their cholesterol-lowering effects. Aim: The aim of this project was to (i) identify a repertoire of proinflammatory mesangial cell AII-inducible mRNAs; (ii) determine if the AII-induced proinflammatory mRNA responses depend on ambient glucose, and (iii) test the anti-inflammatory effectiveness of an ARB, valsartan, either alone or in combination with a statin, simvastatin. Results/Conclusions: Using high-density microarrays and real-time PCR we identified several AII-inducible proinflammatory mesangial genes that exhibited augmented mRNA responses in high-glucose milieu. Valsartan blocked the AII-induced mRNA expression of proinflammatory genes (i.e. MCP-1, LIF and COX-2) maintained in normal and high glucose. These observations add to the mounting evidence that ARBs have anti-inflammatory effects in the kidney, a beneficial effect that may be more important in protecting renal function in diabetic patients. While simvastatin inhibited expression of some mRNAs encoding chemokines/cytokines, it enhanced expression of mRNA encoding COX-2, a key mediator of inflammation. Thus, the non-cholesterol effects of statins on inflammatory responses appear complex.

Copyright © 2009 S. Karger AG, Basel

  Author Contacts

Karol Bomsztyk
UW Medicine Lake Union
Box 358050, University of Washington
Seattle WA 98109 (USA)
Tel. +1 206 616 7949, Fax +1 206 616 8591, E-Mail karolb@u.washington.edu

  Article Information

Received: July 11, 2008
Accepted: January 16, 2009
Published online: February 19, 2009
Number of Print Pages : 13
Number of Figures : 4, Number of Tables : 3, Number of References : 106