Role of renal prostaglandins in normal and nephrotic rats with diet-induced hyperfiltration

Changes in glomerular hemodynamics have been observed in animals and humans after a high-protein feeding. It has been postulated that these changes can induce progressive deterioration of renal function favoring loss of glomerular permselectivity properties and subsequent glomerulosclerosis, especially when the renal mass is already reduced surgically or by a disease process. We studied the consequence of long-term protein supplementation on renal function parameters in normal animals and in animals affected by adriamycin nephrosis, a model of renal damage that closely mimics human "minimal change". We also wanted to investigate whether vasodilatory prostaglandins (PGs) generated at the renal level are responsible for the adaptive hemodynamic changes that follow dietary manipulation in normal animals and in animals with experimental nephrosis. The model of glomerular damage we used is characterized by heavy and persistent proteinuria induced in the rat by adriamycin (ADR). Two isocaloric diets were selected containing 20% and 35% protein. High-protein feeding induced a significant increase in glomerular filtration rate in both normal and nephrotic animals. In normal animals the high-protein diet did not modify the urinary excretion of 6-keto-PGF1 alpha, the stable breakdown product of prostacyclin (PGI2), but significantly reduced urinary excretion of prostaglandin E2. In nephrotic rats, the high-protein diet increased urinary excretion of 6-keto-PGF1 alpha, without modifying urinary excretion of prostaglandin E2. Glomerular synthesis of vasodilatory prostaglandins paralleled the urinary excretion pattern. The cyclooxygenase inhibitor indomethacin effectively inhibited urinary excretion of vasodilatory PGs but did not prevent hyperfiltration in normal animals fed the high-protein diet. At variance, when given to nephrotic animals fed the high-protein diet, indomethacin at a dose that reduced 6-keto-PGF1 alpha and prostaglandin E2 urinary excretion by 84% and 93%, respectively, inhibited hyperfiltration. We conclude that the same hemodynamic changes that occur in normal animals given a high-protein diet also take place when glomeruli are uniformly damaged by a disease process as in ADR nephrosis. However, whereas hyperfiltration in normal animals appears to be independent of renal PGs, in nephrotic animals an enhanced renal synthesis of PGI2 appears to play a crucial role in the adaptive changes responsible for hyperfiltration.