Heat shock protein 70 is necessary to improve mitochondrial bioenergetics and reverse diabetic sensory neuropathy following KU-32 therapy

• Published in: The Journal of pharmacology and experimental therapeutics 2014-02, Vol.348 (2), p.281-292
• Main Authors: Ma, Jiacheng, Farmer, Kevin L, Pan, Pan, Urban, Michael J, Zhao, Huiping, Blagg, Brian S J, Dobrowsky, Rick T
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetic Neuropathies - prevention & control; Dose-Response Relationship, Drug; Drug Discovery and Translational Medicine; Female; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Ganglia, Spinal - pathology; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - blood; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - therapeutic use; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondria - metabolism; Mitochondrial Dynamics - drug effects; Neuritis - prevention & control; Neurons - drug effects; Neurons - enzymology; Neurons - metabolism; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - blood; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - therapeutic use; Novobiocin - administration & dosage; Novobiocin - analogs & derivatives; Novobiocin - blood; Novobiocin - pharmacokinetics; Novobiocin - therapeutic use; Oxidative Phosphorylation - drug effects; Sensory Receptor Cells - drug effects; Sensory Receptor Cells - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.113.210435

Impaired neuronal mitochondrial bioenergetics contributes to the pathophysiologic progression of diabetic peripheral neuropathy (DPN) and may be a focal point for disease management. We have demonstrated that modulating heat shock protein (Hsp) 90 and Hsp70 with the small-molecule drug KU-32 ameliorates psychosensory, electrophysiologic, morphologic, and bioenergetic deficits of DPN in animal models of type 1 diabetes. The current study used mouse models of type 1 and type 2 diabetes to determine the relationship of changes in sensory neuron mitochondrial bioenergetics to the onset of and recovery from DPN. The onset of DPN showed a tight temporal correlation with a decrease in mitochondrial bioenergetics in a genetic model of type 2 diabetes. In contrast, sensory hypoalgesia developed 10 weeks before the occurrence of significant declines in sensory neuron mitochondrial bioenergetics in the type 1 model. KU-32 therapy improved mitochondrial bioenergetics in both the type 1 and type 2 models, and this tightly correlated with a decrease in DPN. Mechanistically, improved mitochondrial function following KU-32 therapy required Hsp70, since the drug was ineffective in diabetic Hsp70 knockout mice. Our data indicate that changes in mitochondrial bioenergetics may rapidly contribute to nerve dysfunction in type 2 diabetes, but not type 1 diabetes, and that modulating Hsp70 offers an effective approach toward correcting sensory neuron bioenergetic deficits and DPN in both type 1 and type 2 diabetes.