Effect of Cyclooxygenase(COX)-1 and COX-2 inhibition on furosemide-induced renal responses and isoform immunolocalization in the healthy cat kidney

Abstract

BackgroundThe role of cyclooxygenase(COX)-1 and COX-2 in the saluretic and renin-angiotensin responses to loop diuretics in the cat is unknown. We propose in vivo characterisation of isoform roles in a furosemide model by administering non-steroidal anti-inflammatory drugs (NSAIDs) with differing selectivity profiles: robenacoxib (COX-2 selective) and ketoprofen (COX-1 selective).ResultsIn this four period crossover study, we compared the effect of four treatments: placebo, robenacoxib once or twice daily and ketoprofen once daily concomitantly with furosemide in seven healthy cats. For each period, urine and blood samples were collected at baseline and within 48 h of treatment starting. Plasma renin activity (PRA), plasma and urinary aldosterone concentrations, glomerular filtration rate (GFR) and 24 h urinary volumes, electrolytes and eicosanoids (PGE2, 6-keto-PGF1α, TxB2), renal injury biomarker excretions [N-acetyl-beta-D-glucosaminidase (NAG) and Gamma-Glutamyltransferase] were measured. Urine volume (24 h) and urinary sodium, chloride and calcium excretions increased from baseline with all treatments. Plasma creatinine increased with all treatments except placebo, whereas GFR was significantly decreased from baseline only with ketoprofen. PRA increased significantly with placebo and once daily robenacoxib and the increase was significantly higher with placebo compared to ketoprofen (10.5 ± 4.4 vs 4.9 ± 5.0 ng ml−1 h−1). Urinary aldosterone excretion increased with all treatments but this increase was inhibited by 75 % with ketoprofen and 65 % with once daily robenacoxib compared to placebo. Urinary PGE2 excretion decreased with all treatments and excretion was significantly lower with ketoprofen compared to placebo. Urinary TxB2 excretion was significantly increased from baseline only with placebo. NAG increased from baseline with all treatments. Immunohistochemistry on post-mortem renal specimens, obtained from a different group of cats that died naturally of non-renal causes, suggested constitutive COX-1 and COX-2 co-localization in many renal structures including the macula densa (MD).ConclusionsThese data suggest that both COX-1 and COX-2 could generate the signal from the MD to the renin secreting cells in cats exposed to furosemide. Co-localization of COX isoenzymes in MD cells supports the functional data reported here.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-015-0598-z) contains supplementary material, which is available to authorized users.

Ketorolac- and warfarin-induced renal toxicity: ultrastructural and biochemical study

“…Results obtained in the present study revealed mild alterations in the kidney function, reflected as a significant increase in urea of KT/WR-treated rats and a significant decrease in the creatinine level of both WR and KT/WR-treated groups. These altered parameters were in accordance with several reports reflecting a disturbed kidney function (Aly et al, 2015;Hörl, 2010;Kim & Joo, 2007;Pelligand et al, 2015) More recently, Lucas et al (2018) reported that NSAIDs increase the risk of developing nephrotoxicity and acute tubular necrosis and they recommended that this condition be well evaluated. The authors concluded that NSAIDs, selective and non-selective, directly interfere with renal function due to prostaglandin inhibition, and suggested acute sodium retention, which is the main cause of the overfilling effect due to arterial hypertension and edema (Chana et al, 2014).…”

CD147 and Cyclooxygenase Expression in Feline Oral Squamous Cell Carcinoma

“…The epitope sequence for the CD147 antibody was proprietary, but personal communication with the manufacturer (Santa Cruz) indicated 79% homology to feline CD147. Feline intestinal goblet cells were selected as a positive control for COX-1 [ 29 ], feline kidney (macula densa) was selected as a positive control tissue for COX-2 [ 30 ] , and feline small intestine was selected as a positive control for CD147 expression [ 31 ]. For negative control purposes, primary antibodies and antiserum were replaced with control rabbit IgG (Millipore Sigma Company, Etobicoke, ON, Canada), control goat IgG, and control rabbit serum (Santa Cruz).…”

“…Positive control tissues were selected based on the published literature. Feline intestinal goblet cells were selected as a positive control for COX-1 [ 29 ], feline kidney (macula densa) was selected for COX-2 expression [ 30 ] , and feline small intestine (enterocytes) was selected as for CD147 expression [ 32 , 33 ]. Positive and negative controls were included in all of the IHC runs.…”

Pathophysiological aspects of nephropathy caused by non-steroidal anti-inflammatory drugs

“…Recent evidence from case-control and retrospective studies suggest that there is no correlation between a higher incidence of hyperkalemia with selective COX-2 inhibitors (the coxibs), as already described in clinical trials of the 1980s, and thus the incidence of hypokalemia with any class of NSAIDs. 4 , 9 , 14 , 17 …”

“…However, in physiological situations, such enzymes are not primary components of the hydroelectrolytic homeostasis generated in the kidneys, since the baseline production rate of prostaglandins is relatively low. 2 , 4 , 11 , 12 , 15 , 17 It has been suggested that the acute sodium retention caused by NSAIDs in healthy elderly is mediated by COX-2 inhibition, while the sudden decrease in GFR is due to COX-1 inhibition. 4 …”