Pioglitazone, a Peroxisome Proliferator Activated Receptor γ Agonist, Decreases Renal Crystal Deposition, Oxidative Stress and Inflammation in Hyperoxaluric Rats

PURPOSE: Kidney stone disease has characteristics similar to those of metabolic syndrome, including inflammation and oxidative stress. The peroxisome proliferator activated receptor γ agonist pioglitazone (AK Scientific, Union, California) is used to treat type 2 diabetes mellitus with an adjunctive effect that improves glycemic control and has anti-inflammatory and antioxidative effects. We investigated the preventive effects of pioglitazone for stone formation in a hyperoxaluric rat model. MATERIALS AND METHODS: We divided Sprague-Dawley® rats into a control group, a 1% ethylene glycol group and a 1% ethylene glycol plus 10 mg/kg pioglitazone group. Blood and 24-hour urine samples, and kidney sections were collected on days 7, 14 and 28. We examined crystal formation using Pizzolato staining and polarized light optical microscopy. We also evaluated cell injury, apoptosis and oxidative stress with N-acetyl-β-glucosaminidase, 8-hydroxydeoxyguanosine and TUNEL assay. Expression of crystal and inflammation related genes was examined by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction. RESULTS: Kidney crystal formation was significantly less in the ethylene glycol plus pioglitazone group than in the ethylene glycol group. Cell injury, apoptosis and oxidative stress markedly decreased after pioglitazone administration. Expression of osteopontin and ED1 for proinflammatory macrophages was lower in the ethylene glycol plus pioglitazone group than in the ethylene glycol group while that of ED2 for anti-inflammatory macrophages was the same in the 2 groups. Linear regression analysis showed a significant change in the correlation coefficient with pioglitazone treatment between Spp1 and Sod1 expression, and the amount of crystals. CONCLUSIONS: Pioglitazone suppressed kidney crystal formation through renal tubular cell protection, and antioxidative and anti-inflammatory effects in hyperoxaluric rats.