title: Protective effects of aliskiren and valsartan in mice with diabetic nephropathy.
abstract: OBJECTIVE
  We investigated whether aliskiren, a direct renin inhibitor, provided protection in a model of diabetic nephropathy in mice and compared its protective effects to valsartan, an angiotensin II type 1 receptor blocker.
  
  
  METHODS
  Hyperglycemia was induced with streptozotocin (STZ, 40 mg/kg/day × 5 days) injection in DBA/2J mice fed on a high fat diet. Mice were treated with either aliskiren (25 mg/kg/day) or valsartan (8 mg/kg/day) for 6 weeks.
  
  
  RESULTS
  Aliskiren and/or valsartan treatment significantly attenuated albuminuria, urinary nephrin excretion and glomerulosclerosis. Aliskiren and/or valsartan prevented reduction of podocin and WT1 protein abundance in diabetic mice. Aliskiren and/or valsartan significantly prevented increased expression of profibrotic growth factors (TGFβ, CTGF and PAI-1), proinflammatory cytokines (MCP-1, TNFα and IL-1β), endoplasmic reticulum (ER) stress markers (CHOP and XBP-1) and lipid accumulation in the kidney of diabetic animals. Aliskiren showed similar efficacy compared to valsartan therapy and dual treatment in some aspects has synergistic protective effects.
  
  
  CONCLUSIONS
  Our study indicates that aliskiren and/or valsartan protects against diabetic kidney disease through multiple mechanisms, including decreasing podocyte injury, activation of profibrotic growth factors and proinflammatory cytokines, ER stress and accumulation of lipids.
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, USA Institute of Hypertension and Kidney Research, Zhongshan School of Medicine, Sun Yat-sen University, China wangwd6@mail.sysu.edu.cn.
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, USA.
authors.forename: Liru
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Howard
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Solis
authors.affiliation: Institute of Hypertension and Kidney Research, Zhongshan School of Medicine, Sun Yat-sen University, China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, USA.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Kidney Disease Section, NIDDK, NIH, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.affiliation: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, USA.
authors.forename: Moshe
authors.initials: M
authors.lastname: Levi
mesh_terms: D000418:Albumins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003404:Creatinine / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005650:Fumarates / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects / Q000473:pathology; D008811:Mice, Inbred DBA; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011507:Proteinuria / Q000150:complications / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan
chemical_list: D000418:Albumins; D000577:Amides; D005650:Fumarates; D008565:Membrane Proteins; D020011:Protective Agents; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D013777:Tetrazoles; C113267:nephrin; C446481:aliskiren; D000068756:Valsartan; D003404:Creatinine; D014633:Valine
keywords: Albuminuria; ER stress; diabetic nephropathy; lipid metabolism; renin inhibition