Different Actions of the Cyclooxygenase 2 Selective Inhibitor Flosulide in Rats with Passive Heymann Nephritis

Abstract

The prostaglandin cyclooxygenase (Cox) exists in two isoforms with different genetic representation. The isoform, which is constitutively expressed (Cox 1), and mediates physiological functions of prostaglandins, and the inducible isoform (Cox 2) which is upregulated by inflammatory stimuli. This study attempts to determine whether a Cox 2 selective inhibitor, flosulide, differs from the mixed type Cox 1 and Cox 2 inhibitor aspirin in respect of renal function and eicosanoid excretion in experimental nephritis. The effects of flosulide and aspirin were studied during the autologous phase of passive Heymann nephritis (PHN) in rats. Female Wistar rats were injected i.v. with 1 ml of Fx1A antiserum at day 1. From day 7 to day 14 they received either aspirin (aspirin, 50 mg/day), flosulide, (0.75 mg/day) or vehicle p.o. The kidney function was evaluated and the animals sacrificed. The kidneys were removed and glomeruli isolated. The glomeruli were incubated in physiological buffer solution. Basal prostaglandin generation was determined in the supernatant. Treatment with flosulide significantly reduced proteinuria as compared to aspirin treatment (64±15 vs. 109±14 mg/24 h, p < 0.05). Plasma protein and albumin levels were significantly lower in the aspirin-treated group than in flosulide-treated animals (4.7±0.26 vs. 5.48±0.08 mg/dl, p < 0.05 and 0.96±0.04 vs. 1.25±0.10 mg/dl, p < 0.05). Glomerular prostaglandin production (6-keto-PGF_1α, TxB₂, Bicyclo-PGE₂) was significantly reduced in aspirin-, but not in flosulide-treated animals. This was mainly due to a reduction of glomerular TxB₂ production by aspirin. Our data demonstrate that a Cox 2 selective inhibitor of prostaglandin formation, flosulide, has beneficial effects on preservation of kidney function in rats with PHN, whereas aspirin has not. These beneficial effects of flosulide possibly result from preservation of the physiological glomerular prostaglandin production. Thus, selective Cox 2 inhibitors might be interesting substances for treatment of nephrotic syndrome.

Plasma lipidomics reveal profound perturbation of glycerophospholipids, fatty acids, and sphingolipids in diet-induced hyperlipidemia

“…Previous studies have shown significantly increased glomerular cyclooxygenase-1 or -2 expression in patient and animal models of glomerulonephritis [11][12][13] and upregulation of glomerular cyclooxygenase-2 expression in patient and animal models of lupus nephritis [13,14]. Cyclooxygenase inhibition has been shown to ameliorate passive Heymann nephritis and lupus nephritis in experimental animals [14][15][16]. Leukotrienes, associated with inflammatory glomerular injury and lipoxygenase product (12-hydroxyeicosatetraenoic acid), mediated angiotensin II and transforming growth factor-β-induced mesangial expansion in diabetic nephropathy (DN) [17].…”

Inhibition of Cyclooxygenases Reduces Complement-Induced Glomerular Epithelial Cell Injury and Proteinuria in Passive Heymann Nephritis

“…In the rat subtotal renal ablation model, the COX-2-selective inhibitor SC58236, reduced proteinuria and glomerulosclerosis to a similar extent as enalapril, while not affecting systemic blood pressure (Wang et al, 2000). In PHN, a COX-2-selective inhibitor, flosulide, was shown to reduce proteinuria, and the reduction was equal in magnitude at low and high doses (Heise et al, 1998;Blume et al, 1999). However, glomerular expression of both COX-1 and -2 proteins was markedly inhibited in rats treated with the high dose of flosulide (Heise et al, 1998;Blume et al, 1999).…”

“…In PHN, a COX-2-selective inhibitor, flosulide, was shown to reduce proteinuria, and the reduction was equal in magnitude at low and high doses (Heise et al, 1998;Blume et al, 1999). However, glomerular expression of both COX-1 and -2 proteins was markedly inhibited in rats treated with the high dose of flosulide (Heise et al, 1998;Blume et al, 1999). Furthermore, flosulide impaired creatinine clearance (Blume et al, 1999).…”

Selective Cyclooxygenase-2 Inhibition Upregulates Renal Cortical α_v Integrin Expression

“…Wang et al [35]have described that the administration of the selective COX-2 inhibitor SC 58236 decreased proteinuria in rats with reduced renal mass. In previous studies, we observed that in rats with PHN the application of the selective COX-2 inhibitor flosulide reduced proteinuria [4, 36]. Because renal COX-2 expression is increased in glomerulonephritis such as lupus nephritis [2], it is possible that COX-2 inhibitors may also alter the natural history of glomerular inflammatory lesions, a finding which is suggested by the development of renal failure in COX-2 knockout mice [37].…”