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Alterations in the Renal Elastin-Elastase System in Type 1 Diabetic Nephropathy Identified by Proteomic Analysis

Visith Thongboonkerd^1,*, Michelle T. Barati^*, Kenneth R. McLeish^*,,||, Charaf Benarafa^¶, Eileen Remold-O’Donnell^¶, Shirong Zheng, Brad H. Rovin^#, William M. Pierce, Paul N. Epstein^, and Jon B. Klein^*,,||

*Core Proteomics Laboratory, Kidney Disease Program, Department of Medicine, and Departments of Biochemistry and Molecular Biology, Pediatrics, and Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky; ^||Veterans Affairs Medical Center, Louisville, Kentucky; ^¶Center for Blood Research and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; and ^#Department of Medicine, Ohio State University School of Medicine, Columbus, Ohio

Correspondence to Dr. Visith Thongboonkerd, Proteomics Center, Medical Molecular Biology Unit, Office for Research and Development, 12^th Floor—Adulyadej Vikrom Building, Siriraj Hospital, Prannok Road, Bangkoknoi, Bangkok 10700, Thailand. Phone: 66-2-4184793; Fax: 66-2-4184793; E-mail: thongboonkerd{at}dr.com

ABSTRACT. Diabetes now accounts for >40% of patients with ESRD. Despite significant progress in understanding diabetic nephropathy, the cellular mechanisms that lead to diabetes-induced renal damage are incompletely defined. For defining changes in protein expression that accompany diabetic nephropathy, the renal proteome of 120-d-old OVE26 transgenic mice with hypoinsulinemia, hyperglycemia, hyperlipidemia, and proteinuria were compared with those of background FVB nondiabetic mice (n = 5). Proteins derived from whole-kidney lysate were separated by two-dimensional PAGE and identified by matrix-assisted laser desorption ionization–time-of-flight (MALDI-TOF) mass spectrometry. Forty-one proteins from 300 visualized protein spots were differentially expressed in diabetic kidneys. Among these altered proteins, expression of monocyte/neutrophil elastase inhibitor was increased, whereas elastase IIIB was decreased, leading to the hypothesis that elastin expression would be increased in diabetic kidneys. Renal immunohistochemistry for elastin of 325-d-old FVB and OVE26 mice demonstrated marked accumulation of elastin in the macula densa, collecting ducts, and pelvicalyceal epithelia of diabetic kidneys. Elastin immunohistochemistry of human renal biopsies from patients with type 1 diabetes (n = 3) showed increased elastin expression in renal tubular cells and the interstitium but not glomeruli. These results suggest that coordinated changes in elastase inhibitor and elastase expression result in increased tubulointerstitial deposition of elastin in diabetic nephropathy. The identification of these coordinated changes in protein expression in diabetic nephropathy indicates the potential value of proteomic analysis in defining pathophysiology.

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