J Korean Med Sci.  2009 Jan;24(Suppl 1):S183-S188. 10.3346/jkms.2009.24.S1.S183.

Effects of Celecoxib and Nordihydroguaiaretic Acid on Puromycin Aminonucleoside-Induced Nephrosis in the Rat

• Lee DW
• Kwak IS
• Lee SB
• Song SH
• Seong EY
• Chung HC
• Yang BY
• Lee MY
• Sol MY

• KMID: 1778160
• DOI: http://doi.org/10.3346/jkms.2009.24.S1.S183

Abstract

The selective cyclooxygenase-2 (COX-2) and 5-lipoxygenase (LOX) inhibitors might inhibit prostaglandin synthesis and reduce proteinuria. The present study was designed to investigate the anti-proteinuric effects of nordihydroguaiaretic acid (NDGA) as compared with celecoxib in puromycin aminonucleoside (PAN) nephrosis rats. Fifty five male Sprague-Dawley rats were divided into 4 groups; A, normal control; B, PAN group; C, PAN+COX-2 inhibitor (celecoxib) group; and D, PAN+5-LOX inhibitor (NDGA) group. After induction of PAN nephrosis through repeated injections of PAN (7.5 and 15 mg/100 g body weight), rats were treated with celecoxib, NDGA, or vehicle for 2 weeks. Twenty four hour urine protein excretions were significantly lower in PAN+celecoxib and PAN+NDGA groups than in PAN group. Serum creatinine (SCr) concentrations and 24 hr urine creatinine clearances (CCr) were not significantly different in the four groups. Electron microscopy showed that podocyte morphology was changed after the induction of PAN nephrosis and was recovered after celecoxib or NDGA administration. Celecoxib significantly recovered the expressions of nephrin, CD2AP, COX-2, and TGF-beta. NDGA also recovered TGF-betaexpression, but did not alter the expressions of nephrin, CD2AP and COX-2. The present study suggested that celecoxib and NDGA might effectively reduce proteinuria in nephrotic syndrome without impairing renal function.

Keyword

Puromycin Aminonucleoside; Proteinuria; Celecoxib; Nordihydroguaiaretic Acid

MeSH Terms

Animals
Anti-Inflammatory Agents, Non-Steroidal/pharmacology
Body Weight
Creatinine/blood
Cyclooxygenase Inhibitors/pharmacology
Male
Microscopy, Electron
Nephrosis/*chemically induced/drug therapy
Nordihydroguaiaretic Acid/*pharmacology
Podocytes/metabolism
Puromycin Aminonucleoside/pharmacology/*toxicity
Pyrazoles/*pharmacology
Rats
Rats, Sprague-Dawley
Sulfonamides/*pharmacology
Time Factors

Figure

• 

  Fig. 1 Schematic of the treatment schedule. After three days of acclimation, test animals were injected intraperitoneally on day 0 with PAN 75 mg/kg, and then 7 days later with 150 mg/kg. Control animals were administered an identical volume of normal saline. After inducing PAN nephrosis, all animals were treated with celecoxib (40 mg/kg/day), NDGA (10 mg/kg/day), or vehicle up to Day 28. Serum and 24 hr urine samples were obtained on days 0, 7, 14, 21, and 28 (▴). All rats were sacrificed on day 28, and kidneys were removed immediately for histological examinations.

• 

  Fig. 2 Effects of celecoxib and NDGA on 24 hr urine protein excretion in PAN-induced nephrosis rats. Twenty four hour urine protein excretion amounts were significantly lower in groups C and D on day 28 than in group B (*p<0.05 vs. group B). Group A, normal controls; group B, a PAN group; group C, a PAN+celecoxib group; group D, a PAN+NDGA group.

• 

  Fig. 3 Representative pathologic features of a PAN and a PAN+celecoxib groups. (A) Light microscopic feature of a glomerulus in PAN group. Small segmental proliferations with matrix expansion and adhesions between the glomerular tuft and Bowman's capsule were observed (PAS stain, ×300). (B) Electron microscopic feature of mild foot processes changes (arrow) such as effacement, fusion and microvilli in PAN group. (C) Light microscopic feature of a glomerulus in PAN+celecoxib group. Slight expansion of mesangial matrix was observed (PAS stain, ×300). (D) Electron microscopic feature of non-specific foot processes changes in PAN+celecoxib group.

• 

  Fig. 4 Effects of celecoxib and NDGA on nephrin, CD2AP, COX-2, and TGF-β mRNA expressions. (A) Nephrin mRNA expressions decreased after administering PAN in PAN group, and restored significantly in PAN+celecoxib group. (B) CD2AP mRNA expressions decreased in PAN group, and restored significantly in PAN+celecoxib group. (C) COX-2 mRNA expressions increased in PAN group, and restored significantly in PAN+celecoxib group. (D) TGF-β mRNA expressions increased in PAN group, and decreased significantly in PAN+celecoxib and PAN+NDGA groups. *p<0.05 vs. normal controls; †p<0.05 vs. PAN group.

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