title: Quantitative proteomic profiling identifies new renal targets of copper(II)-selective chelation in the reversal of diabetic nephropathy in rats.
abstract: This study aimed to identify new diabetic nephropathy (DN)-related proteins and renal targets of the copper(II)-selective chelator, triethylenetetramine (TETA) in streptozotocin-diabetic rats. We used the recently developed iTRAQ technology to compare renal protein profiles among non-diabetic, diabetic, and TETA-treated diabetic rats. In diabetic kidneys, tubulointerstitial nephritis antigen (TINag), voltage-dependent anion-selective channel (VDAC) 1, and VDAC2 were up-regulated in parallel with alterations in expression of proteins with functions in oxidative stress and oxidative phosphorylation (OxPhos) pathways. By contrast, mitochondrial HSP 60, Cu/Zn-superoxide dismutase, glutathione S-transferase alpha3 and aquaporin-1 were down-regulated in diabetic kidneys. Following TETA treatment, levels of D-amino acid oxidase-1, epoxide hydrolase-1, aquaporin-1, and a number of mitochondrial proteins were normalized, with concomitant amelioration of albuminuria. Changes in levels of TINag, collagen VIalpha1, actinin 4alpha, apoptosis-inducing factor 1, cytochrome C, histone H3, VDAC1, and aquaporin-1 were confirmed by Western blotting or immunohistochemistry. Changes in expression of proteins related to tubulointerstitial function, podocyte structure, and mitochondrial apoptosis are implicated in the mechanism of DN and their reversal by TETA. These findings are consistent with the hypothesis that this new experimental therapy may be useful for treatment of DN.
authors.affiliation: School of Biological Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Deming
authors.initials: D
authors.lastname: Gong
authors.forename: Xiuyin
authors.initials: X
authors.lastname: Chen
authors.forename: Martin
authors.initials: M
authors.lastname: Middleditch
authors.forename: Liangdong
authors.initials: L
authors.lastname: Huang
authors.forename: Greeshma
authors.initials: G
authors.lastname: Vazhoor Amarsingh
authors.forename: Shiva
authors.initials: S
authors.lastname: Reddy
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Shaoping
authors.initials: S
authors.lastname: Zhang
authors.forename: Katya
authors.initials: K
authors.lastname: Ruggiero
authors.forename: Anthony R J
authors.initials: AR
authors.lastname: Phillips
authors.forename: Garth J S
authors.initials: GJ
authors.lastname: Cooper
mesh_terms: D000818:Animals; D002412:Cations / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology*; D024142:Collagen Type VI / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000652:urine; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism* / Q000652:urine; D015536:Down-Regulation; D005979:Glutathione Peroxidase / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009395:Nephritis, Interstitial / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D014266:Trientine / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D002412:Cations; D015815:Cell Adhesion Molecules; D002614:Chelating Agents; D024142:Collagen Type VI; D003300:Copper; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D014266:Trientine