Progression of diabetic nephropathy - Insights from cell culture studies and animal models

Nephropathy in patients with type I and II diabetes mellitus is a rapidly i ncreasing problem worldwide. Studies using both glomerular and tubular cell s have delineated some of the consequences induced by acute hyperglycemia. In vitro studies have clearly demonstrated that exposure of cultured renal cells, such as glomerular mesangial cells and proximal tubular epithelial c ells, to elevated glucose concentrations, may alter cell proliferation and/ or extracellular matrix turnover. The latter is effected both directly and indirectly by the alteration of cytokine generation. Furthermore, these in vitro studies have allowed detailed examination of the mechanisms by which exposure of these cells to high ambient glucose concentrations may alter ce ll function. Extension of these studies to the experimental in vivo situati on has confirmed most of the in vitro findings. Important insights gained f rom models of type I diabetes (i.e. streptocotocin-induced diabetes) as wel l as type II diabetes (i.e. Goto-Kakizaki (GK) rats and obese Zucker rats) include: (1) The demonstration that increased glomerular cell proliferation and renal matrix accumulation, driven by TGF-beta and/or PDGF, occur in st reptocotocin-induced diabetes, yet that nephropathy in these rats does not progress to renal failure. (2) The demonstration that prolonged mild type I I diabetes does induce morphological changes characteristic of pre-clinical diabetic nephropathy in GK-rats but does not result in albuminuria or prog ressive renal disease. (3) The demonstration that the association of type I I diabetes with hyperlipidemia in obese Zucker rats results in early podocy te damage and subsequent progression to glomerulosclerosis, tubulointerstit ial damage, and renal insufficiency. Identification of the mediators involv ed in the above processes and in particular of the conditions that will det ermine progression of subclinical morphological changes to overt nephropath y and renal failure will likely result in future novel therapeutic approach es to diabetic nephropathy.