Podocyte injury underlies the progression of focal segmental glomerulosclerosis in the fa/fa Zucker rat

Background. The progression of diabetic nephropathy to chronic renal failur e is based on the progressive loss of viable nephrons. The manner in which nephrons degenerate in diabetic nephropathy and whether the injury could be transferred from nephron to nephron art: insufficiently understood. We stu died nephron degeneration in the falfa Zucker rat. which is considered to b e a model for non-insulin-dependent diabetes Methods. Kidneys of falfa rats with an established decline of renal functio n and of fal+ controls were structurally analyzed by advanced morphological techniques, including serial sectioning. high resolution light microscopy, transmission electron microscopy. cytochemistry. and immunohistochemistry. In addition, tracer studies with ferritin were performed. Results. The degenerative process started in the glomerulus with damage to podocytes. including foot process effacement. pseudocyst formation, and cyt oplasmic accumulation of lysosomal granules and lipid droplets. The degener ation of the nephron followed the tuft adhesion-mediated pathway with misdi rected filtration from capillaries included in the adhesion toward the inte rstitium. This was Followed by the formation of paraglomerular spaces that extended around the entire glomerulus. as well as via the glomerulotubular junction. to the corresponding tubulointerstitium This mechanism appeared t o play a major role in the progression of the segmental glomerular injury t o global sclerosis as well as to the degeneration of the corresponding tubu le. Conclusions. The way a nephron undergoes degeneration in this process assur es that the destructive effects remain confined to the initially affected n ephron. No evidence for a transfer of the disease from nephron to nephron a t the level of the tubulointerstitium was found. Thus. each nephron enterin g this pathway to degeneration appears to start separately with the same in itial injuries at the glomerulus.