Predominant functional roles for thromboxane A2 and prostaglandin E2 during late nephrotoxic serum glomerulonephritis in the rat.
While much is known regarding acute nephrotoxic serum (NTS)-induced glomerular injury, the glomerular dynamics and pathophysiologic mediators of the more relevant chronic autologous phase remain poorly defined. Studies were performed in rats 14 d after injection of rabbit serum (n = 6), NTS in the absence (n = 6), or presence, of a cyclooxygenase inhibitor, ibuprofen (n = 6) or a thromboxane A2 (TxA2) receptor antagonist, L-670,596 (n = 5). A mesangial macrophage/monocyte infiltrate was noted with equal intensity in all NTS-treated rats. Glomerular generation rates of prostaglandin (PG) E2, PGF2a, and TxA2 in nephritic kidneys were dramatically increased as compared to controls. 2 wk after NTS, there was an increase in glomerular plasma flow rate (SNPF), attainment of filtration pressure disequilibrium, and augmentation of net transcapillary hydraulic pressure difference (delta P). Glomerular filtration rate (GFR), however, was reduced, due to a marked fall in the glomerular capillary ultrafiltration coefficient (Kf). Cyclooxygenase inhibition resulted in normalization of glomerular eicosanoid generation rates, amelioration of proteinuria, afferent vasoconstriction, and normalization of SNPF, delta P, Kf, and GFR. Selective antagonism of TxA2 also led to preservation of Kf, but was without effect on SNPF, thereby leading to elevated values for GFR. Thus, in contrast to the pathophysiologic role of arachidonate-lipoxygenase products in the early heterologous phase, PG-mediated vasodilatation and TxA2-induced reductions in Kf and GFR underlie glomerular functional changes during autologous mesangioproliferative glomerulonephritis.
Takahashi
K
K
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Schreiner
G F
GF
Yamashita
K
K
Christman
B W
BW
Blair
I
I
Badr
K F
KF
D000818:Animals; D001794:Blood Pressure; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000502:physiology*; D005919:Glomerular Filtration Rate; D005921:Glomerulonephritis / Q000503:physiopathology*; D006400:Hematocrit; D008297:Male; D010972:Platelet Activating Factor / Q000378:metabolism; D011507:Proteinuria / Q000503:physiopathology; D051381:Rats; D013928:Thromboxane A2 / Q000502:physiology*; D014655:Vascular Resistance
D010972:Platelet Activating Factor; D013928:Thromboxane A2; D015237:Dinoprost; D015232:Dinoprostone