Jl. Wang et al., A selective cyclooxygenase-2 inhibitor decreases proteinuria and retards progressive renal injury in rats, KIDNEY INT, 57(6), 2000, pp. 2334-2342
Background. We have previously shown that cyclooxygenase-2 (COX-2) expressi
on is low in the renal cortex of adult rats, but is increased in macula den
sa/cortical thick ascending limb and in glomerular podocytes after subtotal
renal ablation.
Methods. To evaluate the functional consequences of this increased COX-2 ex
pression, male rats were subjected to subtotal renal ablation and divided i
nto four groups: (I) treatment with the selective COX-2 inhibitor SC58236,
(2) treatment with vehicle, (3) treatment with the angiotensin-converting e
nzyme inhibitor enalapril, and (4) treatment with enalapril + SC58236. The
administration of drugs was begun on the third day after ablation and conti
nued for 6 to 10 weeks.
Results. Within one week after ablation, vehicle-treated rats developed hyp
ertension. Although enalapril led to significant reductions in blood pressu
re, either alone or in combination with the COX-2 inhibitor, SC58236 alone
did not significantly alter ablation-induced hypertension. However, the SC5
8236-treated animals exhibited levels of proteinuria at six weeks after abl
ation that were comparable to those seen with enalapril (vehicle, 47 +/- 4;
enalapril, 27 +/- 2; SC58236, 30 +/- 2 mg/day; N = 7, P < 0.01, each group
compared with vehicle), and continued SC58236 treatment led to persistent r
eductions in proteinuria at 10 weeks after renal ablation (vehicle, 77 +/-
4; SC58236, 50 +/- 4 mg/day; N = 6, P < 0.01). SC58236 treatment also signi
ficantly reduced the percentage of glomeruli exhibiting segmental or global
sclerosis at 10 weeks (32.6 +/- 7.8% vs. 10.9 +/- 2.8%, N = 6, P < 0.03).
Furthermore, SC58236 treatment partially inhibited increases in transformin
g growth factor-beta 1 mRNA expression and increases in collagen III and co
llagen IV mRNA expression.
Conclusions. These studies indicate that chronic treatment with a specific
COX-2 inhibitor may retard the progression of progressive renal injury, and
suggest that such compounds can be used in combination with angiotensin-co
nverting enzyme inhibitors. Further studies are required to determine the m
echanism by which COX-2 inhibition is renoprotective.