Selective inhibition of platelet thromboxane generation with low-dose aspirin does not protect rats with reduced renal mass from the development of progressive disease.
Rats with extensive renal mass reduction develop hypertension, proteinuria and progressive glomerulosclerosis. Previous studies have demonstrated that these changes are associated with an increased urinary excretion of thromboxane compared with normal rats and that the administration of a thromboxane synthetase inhibitor prevents glomerulosclerosis and progressive renal function deterioration. On this basis it has been speculated that the thromboxane synthetase inhibitor, by inhibiting platelet thromboxane, reduces platelet aggregation and prevents the generation of substances that can influence glomerular functional properties. Because the thromboxane synthetase inhibitor also inhibits thromboxane synthesis by resident glomerular cells and lowers blood pressure in these animals, the question of whether platelet thromboxane is indeed the factor implicated in the development of renal disease after renal ablation remains unanswered. To address this issue the authors administered at different time intervals from the surgical procedure a low-dose of oral aspirin (ASA) to rats with remnant kidney. This approach resulted in selective inhibition of platelet cyclooxygenase leading to an almost complete prevention of platelet thromboxane generation. Low-dose ASA spared renal cyclooxygenase as documented by a lack of significant inhibition of glomerular and urinary 6-keto-PGF1 alpha and did not lower blood pressure. Renal function studies showed that low-dose ASA, despite inhibiting platelet aggregation, had no effect on proteinuria and progressive renal insufficiency irrespectively if administered late (ie, 80 days after surgery) and given daily for all the observation period (ie, 20 days) or earlier in the course of the disease (ie, 40 and 10 days after surgery). Histologic data showed that the degree of glomerulosclerosis and tubulo-interstitial damage was not significantly different in rats with reduction of renal mass alone compared with rats with remnant kidney given low-dose ASA. In conclusion, the present findings indicate that inhibition of platelet aggregation and thromboxane formation does not prevent the progressive glomerulosclerosis that develops in rats with surgical reduction of renal mass. It is suggested that the beneficial results obtained previously in the same model by the use of a thromboxane synthesis inhibitor must be attributed either to an effect on resident glomerular cell thromboxane synthesis or to lowering systemic blood pressure.
Zoja
C
C
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Benigni
A
A
Livio
M
M
Bergamelli
A
A
Orisio
S
S
Abbate
M
M
Bertani
T
T
Remuzzi
G
G
D000818:Animals; D001241:Aspirin / Q000008:administration & dosage* / Q000494:pharmacology; D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism; D007668:Kidney / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D007674:Kidney Diseases / Q000097:blood / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000648:ultrastructure; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011507:Proteinuria; D051381:Rats; D011919:Rats, Inbred Strains; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology
D010975:Platelet Aggregation Inhibitors; D013929:Thromboxane B2; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin