From the Periphery of the Glomerular Capillary Wall Toward the Center of Disease

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FIG. 1.
FIG. 1.

Overview of the mechanisms of podocyte injury leading to diabetic nephropathy. Metabolic factors in the diabetic milieu (TGF-β, high glucose, glycated proteins, ROS, and ANG II) and hemodynamic factors (via mechanical stretch) converge on the podocyte to increase VEGF and ANG II production. Other effects include upregulation of the TGF-β type II receptor and downregulation of the cell surface α3β1 integrins. Podocyte-derived VEGF operating in an autocrine loop, perhaps via VEGFR-1 signaling, stimulates the production of α3(IV) collagen, leading to GBM thickening, and suppresses the expression of nephrin, favoring apoptosis and foot process widening/effacement. Paracrine actions of VEGF on the endothelium may increase glomerular capillary permeability and relax afferent arteriolar tone (through endothelial nitric oxide synthase), generating hemodynamic forces that can injure podocytes. ANG II also suppresses nephrin expression, and it decreases production of the negatively charged HSPG. ANG II and high glucose upregulate the TGF-β type II receptor and may augment the podocyte’s response to paracrine TGF-β, such as that coming from the mesangial cell. The TGF-β/type II receptor interaction stimulates extracellular matrix production by the podocyte (contributing to GBM thickening) and by the mesangium (leading to mesangial matrix expansion). The TGF-β system in the podocyte also promotes apoptosis and decreases integrin expression, which can lead to podocyte detachment and podocyturia. As the results of the above processes, the podocytopenia, foot process widening with loss of nephrin, GBM dysfunction, decreased HSPG, and hemodynamic stress all provoke or exacerbate diabetic proteinuria. Worsening proteinuria coupled with profibrotic stimuli (exemplified by the TGF-β system) induce glomerulosclerosis and tubulointerstitial fibrosis, leading relentlessly to progressive renal insufficiency.

This Article

  1. Diabetes vol. 54 no. 6 1626-1634