American Journal of Kidney Diseases
Volume 54, Issue 4 , Pages 653-664, October 2009

Epithelial-Mesenchymal Transition as a Potential Explanation for Podocyte Depletion in Diabetic Nephropathy

  • Yukinari Yamaguchi, MD

      Affiliations

    • First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
    • ,
  • Masayuki Iwano, MD

      Affiliations

    • First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
    • Corresponding Author InformationAddress correspondence to Masayuki Iwano, MD, First Department of Internal Medicine, Nara Medical University, 840 Shijo, Kashihara, Nara 634-8522, Japan
    • ,
  • Daisuke Suzuki, MD

      Affiliations

    • Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
    • ,
  • Kimihiko Nakatani, MD

      Affiliations

    • First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
    • ,
  • Kuniko Kimura, MD

      Affiliations

    • First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
    • ,
  • Koji Harada, MD

      Affiliations

    • First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
    • ,
  • Atsushi Kubo, MD

      Affiliations

    • First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
    • ,
  • Yasuhiro Akai, MD

      Affiliations

    • First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
    • ,
  • Masao Toyoda, MD

      Affiliations

    • Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
    • ,
  • Masao Kanauchi, MD

      Affiliations

    • First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
    • ,
  • Eric G. Neilson, MD

      Affiliations

    • Department of Medicine and Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN
    • ,
  • Yoshihiko Saito, MD

      Affiliations

    • First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan

Received 16 October 2008; accepted 7 May 2009. published online 21 July 2009.

Background

Depletion of glomerular podocytes is an important feature of progressive diabetic nephropathy. Although the most plausible explanation for this podocyte depletion is detachment from the glomerular basement membrane after cellular apoptosis, the mechanism is unclear. Fibroblast-specific protein 1 (FSP1; encoded by the S100A4 gene) is a member of the S100 family of calcium-binding proteins and is constitutively expressed in the cytoplasm of tissue fibroblasts or epithelial cells converted into fibroblasts by means of epithelial-mesenchymal transition.

Study Design

Retrospective cross-sectional analysis.

Settings & Participants

109 patients with type 2 diabetes mellitus, of whom 43 (39%) underwent kidney biopsy.

Predictor

Clinical stage (4 categories) and histological grade (5 categories) of diabetic nephropathy.

Outcome

FSP1 expression in podocytes in urine and glomeruli in kidney biopsy specimens.

Measurements

Immunohistochemistry, real-time polymerase chain reaction, and in situ hybridization.

Results

38 of 109 patients (35%) were normoalbuminuric, 16 (15%) had microalbuminuria, 8 (7%) had macroalbuminuria, and 47 (43%) had decreased kidney function. Approximately 95% of podocytes in urine sediment were not apoptotic, and 86% expressed FSP1. The number of FSP1-positive podocytes in urine sediment was significantly larger in patients with macroalbuminuria than in those with normoalbuminuria (P = 0.03). Intraglomerular expression of FSP1 occurred almost exclusively in podocytes from patients with diabetes, and the number of FSP1-positive podocytes was larger in glomeruli showing diffuse mesangiopathy than in those showing focal mesangiopathy (P = 0.01). The number also was larger in glomeruli with nodular lesions than in those without nodular lesions (P < 0.001). FSP1-positive podocytes selectively expressed Snail1 and integrin-linked kinase, a known trigger for epithelial-mesenchymal transition.

Limitations

Nonrepresentative study population.

Conclusions

These results suggest that the appearance of FSP1 in podocytes of patients with diabetes is associated with more severe clinical and pathological findings of diabetic nephropathy, perhaps because of induction of podocyte detachment through epithelial-mesenchymal transition–like phenomena.

Index Words: Podocyte, diabetes, nephropathy, epithelial-mesenchymal transition, fibroblast-specific protein 1

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 Originally published online as doi: 10.1053/j.ajkd.2009.05.009 on July 21, 2009.

PII: S0272-6386(09)00832-4

doi:10.1053/j.ajkd.2009.05.009

Refers to article:

  • Epithelial-Mesenchymal Transition and Podocyte Loss in Diabetic Kidney Disease

    Kimberly Reidy, Katalin Susztak
    American Journal of Kidney Diseases October 2009 (Vol. 54, Issue 4, Pages 590-593)

American Journal of Kidney Diseases
Volume 54, Issue 4 , Pages 653-664, October 2009

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