Podocyte Detachment and Reduced Glomerular Capillary Endothelial Fenestration in Human Type 1 Diabetic Nephropathy

Abstract

The aim of this study was to investigate the structural characteristics of podocytes and endothelial cells in diabetic nephropathy. We studied 18 patients with type 1 diabetes (seven normoalbuminuric, six microalbuminuric, and five proteinuric), and six normal control subjects. Groups were not different for age. Type 1 diabetic groups were not different for diabetes duration or age at diabetes onset. Podocyte foot process width (FPW), fraction of glomerular basement membrane (GBM) surface with intact nondetached foot processes (IFP), fraction of glomerular capillary luminal surface covered by fenestrated endothelium [S S (Fenestrated/cap)] and classic diabetic glomerulopathy lesions were morphometrically measured. Albumin excretion (AER) and glomerular filtration (GFR) rates were also measured. GFR correlated inversely and AER directly with GBM and mesangial measurements in diabetic patients. FPW correlated inversely with GFR (r ‫؍‬ ؊0.71, P ‫؍‬ 0.001) and directly with AER (r ‫؍‬ 0.66, P ‫؍‬ 0.003), GBM, and mesangial parameters. The GBM fraction covered by IFP was decreased in proteinuric versus control subjects (P ‫؍‬ 0.001), normoalbuminuric patients (P ‫؍‬ 0.0002) and microalbuminuric patients (P ‫؍‬ 0.04) and correlated with renal structural and functional parameters, including AER (r ‫؍‬ ؊0.52, P ‫؍‬ 0.03). Only 78% of GBM was covered by IFP in proteinuric patients. S S (Fenestrated/cap) was reduced in normoalbuminuric (P ‫؍‬ 0.03), microalbuminuric (P ‫؍‬ 0.03), and proteinuric (P ‫؍‬ 0.002) patients versus control subjects. S S (Fenestrated/cap) correlated with mesangial fractional volume per glomerulus (r ‫؍‬ ؊0.57, P ‫؍‬ 0.01), IFP (r ‫؍‬ 0.61, P ‫؍‬ 0.007), and FPW (r ‫؍‬ ؊0.58, P ‫؍‬ 0.01). These novel studies document that podocyte detachment and diminished endothelial cell fenestration are related to classical diabetic nephropathy lesions and renal function in type 1 diabetic patients and support a need for further studies of podocyte/GBM adherence and podocyte/endothelial cell functional interactions in diabetic nephropathy. Diabetes 56:2155-2160, 2007 S trong correlations between morphometric measures of mesangial expansion and glomerular basement membrane (GBM) width and functional parameters in diabetic nephropathy have long been known (1-2). More recently, however, interest in the possible role of podocytes in the development and/or progression of diabetic nephropathy has grown (3). Podocytes are important in maintaining glomerular permselectivity, and the development of proteinuria is associated with morphological changes in these cells, including foot process effacement (4). Podocyte detachment and GBM denudation have been documented in diverse renal conditions associated with severe proteinuria, such as idiopathic focal and segmental glomerulosclerosis (FSGS), puromycin nephrosis, amyloidosis, and reflux nephropathy (5-8). Foot process effacement and decreased podocyte number and/or density per glomerulus have been reported in patients with type 1 and type 2 diabetes (9 -14). There is, how...

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