title: Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice.
abstract: Heat shock proteins (HSPs) are induced by cellular stress and function as molecular chaperones that regulate protein folding. Diabetes impairs the function/expression of many HSPs, including HSP70 and HSP90, key regulators of pathological mechanisms involved in diabetes complications. Therefore, we investigated whether pharmacological HSP90 inhibition ameliorates diabetes-associated renal damage and atheroprogression in a mouse model of combined hyperglycemia and hyperlipidemia (streptozotocin-induced diabetic apolipoprotein E-deficient mouse). Treatment of diabetic mice with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG, 2 and 4 mg/kg, 10 weeks) improved renal function, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leukocyte infiltration, and fibrosis), and expression of proinflammatory and profibrotic genes. Furthermore, DMAG significantly reduced atherosclerotic lesions and induced a more stable plaque phenotype, characterized by lower content of lipids, leukocytes, and inflammatory markers, and increased collagen and smooth muscle cell content. Mechanistically, the renoprotective and antiatherosclerotic effects of DMAG are mediated by the induction of protective HSP70 along with inactivation of nuclear factor-κB (NF-κB) and signal transducers and activators of transcription (STAT) and target gene expression, both in diabetic mice and in cultured cells under hyperglycemic and proinflammatory conditions. In conclusion, HSP90 inhibition by DMAG restrains the progression of renal and vascular damage in experimental diabetes, with potential implications for the prevention of diabetes complications.
authors.affiliation: Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain.
authors.forename: Iolanda
authors.initials: I
authors.lastname: Lazaro
authors.affiliation: Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Madrid, Spain.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Oguiza
authors.affiliation: Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Madrid, Spain.
authors.forename: Carlota
authors.initials: C
authors.lastname: Recio
authors.affiliation: Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain.
authors.forename: Beñat
authors.initials: B
authors.lastname: Mallavia
authors.affiliation: Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Julio
authors.initials: J
authors.lastname: Madrigal-Matute
authors.affiliation: Department of Pathology, Hospital Clinico San Carlos, Madrid, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Blanco
authors.affiliation: Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.affiliation: Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain.
authors.forename: Jose-Luis
authors.initials: JL
authors.lastname: Martin-Ventura
authors.affiliation: Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Madrid, Spain cgomez@fjd.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gomez-Guerrero
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D016227:Benzoquinones / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047029:Lactams, Macrocyclic / Q000627:therapeutic use; D007928:Lethal Dose 50; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D016328:NF-kappa B; D012333:RNA, Messenger; D050791:STAT Transcription Factors; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin