Targeting HSP90 ameliorates nephropathy and atherosclerosis through suppression of NF-κB and STAT signaling pathways in diabetic mice

Iolanda Lazaro, Ainhoa Oguiza, Carlota Recio, Beñat Mallavia, Julio Madrigal-Matute, Julia Blanco, Jesus Egido, Jose Luis Martin-Ventura, Carmen Gomez-Guerrero

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3600-3613
Number of pages14
JournalDiabetes
Volume64
Issue number10
DOIs
StatePublished - Oct 2015

Fingerprint

17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
Transducers
Atherosclerosis
Kidney
Diabetes Complications
Leukocytes
HSP90 Heat-Shock Proteins
Molecular Chaperones
HSP70 Heat-Shock Proteins
Albuminuria
Protein Folding
Apolipoproteins E
Streptozocin
Heat-Shock Proteins
Hyperlipidemias
Hyperglycemia
Smooth Muscle Myocytes
Blood Vessels
Cultured Cells
Fibrosis

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Targeting HSP90 ameliorates nephropathy and atherosclerosis through suppression of NF-κB and STAT signaling pathways in diabetic mice. / Lazaro, Iolanda; Oguiza, Ainhoa; Recio, Carlota; Mallavia, Beñat; Madrigal-Matute, Julio; Blanco, Julia; Egido, Jesus; Martin-Ventura, Jose Luis; Gomez-Guerrero, Carmen.

In: Diabetes, Vol. 64, No. 10, 10.2015, p. 3600-3613.

Research output: Contribution to journalArticle

Lazaro, I, Oguiza, A, Recio, C, Mallavia, B, Madrigal-Matute, J, Blanco, J, Egido, J, Martin-Ventura, JL & Gomez-Guerrero, C 2015, 'Targeting HSP90 ameliorates nephropathy and atherosclerosis through suppression of NF-κB and STAT signaling pathways in diabetic mice', Diabetes, vol. 64, no. 10, pp. 3600-3613. https://doi.org/10.2337/db14-1926
Lazaro, Iolanda ; Oguiza, Ainhoa ; Recio, Carlota ; Mallavia, Beñat ; Madrigal-Matute, Julio ; Blanco, Julia ; Egido, Jesus ; Martin-Ventura, Jose Luis ; Gomez-Guerrero, Carmen. / Targeting HSP90 ameliorates nephropathy and atherosclerosis through suppression of NF-κB and STAT signaling pathways in diabetic mice. In: Diabetes. 2015 ; Vol. 64, No. 10. pp. 3600-3613.
@article{c043d8b121344f12b7671049cc92cc92,
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.",
author = "Iolanda Lazaro and Ainhoa Oguiza and Carlota Recio and Be{\~n}at Mallavia and Julio Madrigal-Matute and Julia Blanco and Jesus Egido and Martin-Ventura, {Jose Luis} and Carmen Gomez-Guerrero",
year = "2015",
month = "10",
doi = "10.2337/db14-1926",
language = "English (US)",
volume = "64",
pages = "3600--3613",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "10",

}

TY - JOUR

T1 - Targeting HSP90 ameliorates nephropathy and atherosclerosis through suppression of NF-κB and STAT signaling pathways in diabetic mice

AU - Lazaro, Iolanda

AU - Oguiza, Ainhoa

AU - Recio, Carlota

AU - Mallavia, Beñat

AU - Madrigal-Matute, Julio

AU - Blanco, Julia

AU - Egido, Jesus

AU - Martin-Ventura, Jose Luis

AU - Gomez-Guerrero, Carmen

PY - 2015/10

Y1 - 2015/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84953343433&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84953343433&partnerID=8YFLogxK

U2 - 10.2337/db14-1926

DO - 10.2337/db14-1926

M3 - Article

C2 - 26116697

AN - SCOPUS:84953343433

VL - 64

SP - 3600

EP - 3613

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 10

ER -