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

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 Snaill and integrin-linked kinase, a known trigger for epithelial-mesenchymal transition. Limitations: Nonrepresentative study population. Conclusions: These results suggest that the appearance of FSPi 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. Am J Kidney Dis 54:653-664. 2009 by the National Kidney Foundation, Inc.