In view of the potential role of prostaglandins (PGs) in development of glo
merular hyperfiltration leading to diabetic nephropathy, we studied the tem
poral relationship of the activity of cytosolic phospholipase A(2) (cPLA(2)
), a rate-limiting enzyme for eicosanoid biosynthesis, with hyperfiltration
and the histological changes in glomeruli using OLETF rats, a model for no
n-insulin-dependent diabetes mellitus (NIDDM). Diabetes mellitus and associ
ated histopathological changes, which developed spontaneously by 30-46 week
s after birth of OLETF rats, were accompanied by approximately 65% increase
in glomerular cPLA(2) activity that showed significant correlations with e
levated plasma glucose levels and creatinine clearance. Moreover, mesangial
cells cultured for 5 days with high glucose exhibited approximately 2-fold
higher cPLA(2) activity than those cultured with physiologic level of gluc
ose. These data suggest that increased glomerular cPLA(2) activity leads to
production of PGs, which may promote the progression of early diabetic glo
merular hyperfiltration and subsequent diabetic nephropathy.