Early mechanisms of renal injury in hypercholesterolemic or hypertriglyceridemic rats

Hyperlipidemia in conjunction with uninephrectomy leads to renal injury in rats. It is unknown whether this is due to mesangial cell or podocyte injur y and whether the injuries induced by hypercholesterolemia and hypertriglyc eridemia share a similar pathogenesis. Therefore, renal effects of hypercho lesterolemia were studied in male rats with dietary hypercholesterolemia co mpared with rats on a regular diet. Renal effects of hypertriglyceridemia w ere studied in female Nagase analbuminemic rats (NAR). Hypertriglyceridemia was reduced in NAR by ovariectomy. Both models were studied after uninephr ectomy or sham operation. Dietary hypercholesterolemia had little effect on plasma triglycerides, whereas ovariectomy in the NAR had no effect on plas ma cholesterol. However, an increase in intermediate density lipoprotein ch olesterol was common to both models. Dietary hypercholesterolemia and unine phrectomy separately induced a similar increase in proteinuria after 13 wk, which was additive when these interventions were combined. At this stage, only a minimal increase was present in glomerular cu-smooth muscle actin st aining, a marker of mesangial cell activation, or in mesangial matrix expan sion. Moreover, platelet-derived growth factor-B chain, a marker of mesangi al cell proliferation, was not increased. However, podocyte injury was prom inent as evidenced by podocytic de novo expression of desmin and ultrastruc tural changes. Glomerular macrophage counts were increased by hypercholeste rolemia but not by uninephrectomy, and were not related to the level of pro teinuria. Hypertriglyceridemia and uninephrectomy in female NAR induced an increase in proteinuria after 24 wk, which was also associated with an incr ease in podocyte desmin expression without any mesangial activation and pro liferation or matrix accumulation. Hypertriglyceridemia, proteinuria, and t he increase in desmin staining were largely prevented by ovariectomy. Inter stitial myofibroblast activation and tubulointerstitial injury accompanied proteinuria in both models. These findings indicate that both hypercholeste rolemia and hypertriglyceridemia aggravate renal injury primarily via podoc yte rather than via mesangial cell damage. Such podocyte injury is accompan ied by tubulointerstitial cell activation and injury.