The Preventive Role of Pioglitazone in Glycerol-Induced Acute Kidney Injury in Rats during Two Different Treatment Periods

Abstract

Background: Acute kidney injury is the most life-threatening complication of rhabdomyolysis. Glycerol is commonly used to induce this injury. The aim was to investigate the renoprotective effects of pioglitazone and the possible advantage of administering the drug for a longer period.

Methods: Twenty-four male Albino Wistar rats were randomly divided into 4 groups (n=6/group): (A) control, (B) glycerol (50%, 10 mL/kg intramuscularly), (C) glycerol+pioglitazone (10 mg/kg orally for 3 days), and (D) glycerol+pioglitazone (for 6 days). Serum urea and creatinine levels were measured to assess the renal function. Reduced glutathione (GSH) levels and histological alterations were also measured. Statistical analysis was performed using Prism (version 6). The numerical data were evaluated by ANOVA, followed by the Tukey tests. The categorical data were evaluated by the Mann-Whitney test and the Fisher exact tests. P<0.05 was considered significant.

Results: In the glycerol-injected rats, the serum urea and creatinine levels were increased (P<0.001), while the GSH levels were decreased (P<0.001) compared to Group A. The nephrotoxicity showed significant tubular (P=0.01) and glomerular (P=0.02) injuries. In the pioglitazone-treated rats, the changes in the serum biomarkers and in the GSH levels were reversed in Group C (P=0.01) and in Group D (P=0.01). The microscopic examinations of the kidneys also showed some improvement. No obvious statistically significant difference was found between these 2 preventive groups in most studied features.

Conclusion: These results indicate that pioglitazone might have nephroprotective effects in this injury model. Pioglitazone succeeded in producing this effect within 3 days. Doubling the drug administration period did not produce any significant superior benefit.

Keywords: Acute kidney injury; Glycerol; Kidney; Pioglitazone; Reduced glutathione; Rhabdomyolysis.

Figure 1

Effects of pioglitazone on serum urea and creatinine levels and on GSH levels in the control group, the glycerol-injected group (GLY), the preventive group treated with pioglitazone for 3 days (GLY+PIO 3days), and the preventive group treated with pioglitazone for 6 days (GLY+PIO 6 days). Values are expressed as mean±SEM. *** P<0.001 compared with the control group; # P<0.05, ## P=0.01 compared with the GLY Group; ●●● P<0.001 compared with Group A; ♦♦♦ P<0.001 compared with Group A; GSH: Glutathione; GLY: Glycerol; PIO: Pioglitazone.

Figure 2

Macroscopic evaluation of the kidney sections in the different groups. (A) Normal macroscopic appearance in the control group A. (B) kidneys are bigger with noticeable medullary congestion and edema and a pale pink cortex (Group B). (C) and (D) Morphological changes are improved in the preventive groups of C and D.

Figure 3

Light microscopic evaluation of the renal tissues stained with hematoxylin and eosin. (a1 ×20) and (a2) Normal histology of the kidney tissues, showing normal glomerulus (red arrow) and normal tubules (yellow arrow) (Group A). (b1) and (b2) Kidney sections of Group B, showing glomerular deformation (red arrow), tubular dilatation, vacuolation, swelling, and degeneration of their lined epithelial cells (yellow arrows), vascular congestion (orange arrow), inflammatory cell infiltration (blue arrow), and fibrinoid dystrophy (green triangle) (×20). (c1, c2) and (d1, d2) Kidney sections of Group C and Group D, respectively, showing the enhancement in tubular and glomerular injuries and other pathologic alterations. The red star represents the hyaline dystrophy (×20).