Molecular Mechanisms of Diabetic Nephropathy:Dickkopf-1 Signaling Components and Renal Fibrosis

  • Lin, Chun-Liang (PI)
  • Wang, Feng Sheng (CoPI)

Project: National Health Research InstitutesNational Health Research Institutes Grants Research

Project Details

Abstract

Molecular Mechanisms of Diabetic Nephropathy: Dickkopf-1 Signaling Components and Renal Fibrosis (Key words: DKK1, diabetic nephropathy, apoptosis, fibrosis, mesangial cells) Diabetic nephropathy is a leading cause of end-stage renal disease in Taiwan. Intense fibrotic matrix accumulation in renal glomeruli that impairs renal function contributes to the pathogenesis of diabetic nephropathy [1]. We have found that disturbed Wnt/b-catenin signaling participates in high glucose-mediated renal cell apoptosis and renal dysfunction [2,3]. Dickkopf-1 (DKK1), a Wnt inhibitor, reportedly controls remodeling of various tissue types. Modulations of Wnt inhibitor action are creative strategies beneficial for alleviates tissue deterioration [4-6]. The biological significance of DKK1 in high glucose-dysregulated renal tissue homeostasis has not been tested. We preliminarily found that high glucose induced fibrosis-promoting factor TGF-b1 and fibronectin in association with upregulated DKK1 and receptor Kremen2 expression of renal mesangial cells. Interestingly, in vivo knock down of DKK1 alleviated the deleterious actions of high glucose on renal tissue in diabetic rats [7]. We hypothesize that DKK1 is an emerging renal-deleterious factor that accelerates renal cell apoptosis and fibrosis in high glucose-stressed renal tissue microenvironments. Modulation of DKK1 signaling may be an innovative strategy for preventing diabetic nephropathy. The rationale and specific aims of the current project are outlined below: Specific aim 1: We plan to explore DKK/Wnt functional genomic profiles of diabetic renal tissue; and use laser capture microdissection technology to isolated specific renal tissue micreoenvironment then validate the expression of DKK1 signaling components. Specific aim 2: We attempt to delineate pathologic role of DKK1 signaling components in high glucose-induced fibrosis and apoptosis of renal cells. We also investigate which signaling transduction responsible for high glucose induction of DKK1 transcription and DKK1-mediated renal cell dysfunction. Specific aim 3: We intend to explore strategies for in vivo knock down of DKK1 signaling components and attenuate diabetes-mediated renal dysfunction. We also investigate proteome-wide mechanism underlying DKK1 modulation of diabetes-induced renal tissue remodeling. Anticipated results: We anticipate that control of DKK1 signaling in renal tissue will be an innovative potential for preventing renal tissue against high glucose stress

Project IDs

Project ID:PG9901-0778
External Project ID:NHRI-EX99-9942SI
StatusFinished
Effective start/end date01/01/1031/12/10

Keywords

  • manpower of dentists
  • oral disease
  • human resource
  • sexual discrimination
  • undergraduate dental education
  • postgraduate dental education

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