title: High ambient glucose augments angiotensin II-induced proinflammatory gene mRNA expression in human mesangial cells: effects of valsartan and simvastatin.
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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: UW Medicine Lake Union Research, University of Washington, Seattle, WA 98109, USA.
authors.forename: Masayo
authors.initials: M
authors.lastname: Naito
authors.forename: Ananth
authors.initials: A
authors.lastname: Shenoy
authors.forename: Isao
authors.initials: I
authors.lastname: Aoyama
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Koopmeiners
authors.forename: Radko
authors.initials: R
authors.lastname: Komers
authors.forename: H William
authors.initials: HW
authors.lastname: Schnaper
authors.forename: Karol
authors.initials: K
authors.lastname: Bomsztyk
mesh_terms: D000804:Angiotensin II / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D005947:Glucose / Q000633:toxicity*; D006439:Hemodynamics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism; D007249:Inflammation; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; D019821:Simvastatin; D014633:Valine; D005947:Glucose