Spironolactone inhibits hyperglycemia-induced podocyte injury by attenuating ROS production
| Autor: | Hideko Noguchi, Kiichiro Fujisaki, Jiro Toyonaga, Kazuhiko Tsuruya, Masatomo Taniguchi, Kohsuke Masutani, Hideki Yotsueda, Mitsuo Iida, Makoto Hirakawa, Hirofumi Ikeda |
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| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty Blotting Western Spironolactone medicine.disease_cause Diabetes Mellitus Experimental Podocyte Rats Sprague-Dawley Renin-Angiotensin System Diabetic nephropathy chemistry.chemical_compound Mineralocorticoid receptor Internal medicine medicine Animals RNA Messenger Mineralocorticoid Receptor Antagonists Transplantation NADPH oxidase biology Podocytes Reverse Transcriptase Polymerase Chain Reaction business.industry NADPH Oxidases Streptozotocin medicine.disease Rats Oxidative Stress Proteinuria medicine.anatomical_structure Endocrinology chemistry Nephrology Hyperglycemia biology.protein Synaptopodin Reactive Oxygen Species business Nicotinamide adenine dinucleotide phosphate Oxidative stress medicine.drug |
| Zdroj: | Nephrology Dialysis Transplantation. 26:2475-2484 |
| ISSN: | 1460-2385 0931-0509 |
| DOI: | 10.1093/ndt/gfq750 |
| Popis: | Background Accumulating evidence suggests that mineralocorticoid receptor (MR) blockade effectively reduces proteinuria in diabetic nephropathy although the renin-angiotensin-aldosterone system is generally suppressed in diabetes. The present study was designed to confirm the antiproteinuric effect of MR blockade in diabetic rats and elucidate its mechanism. Methods The present study investigated whether MR blockade inhibits hyperglycemia-induced podocyte injury, focusing on the involvement of reactive oxygen species (ROS) production, in diabetic rats and cultured podocytes. Sprague-Dawley rats were divided into three groups: control, streptozotocin (STZ; 75 mg/kg)-injected diabetic and STZ treated with spironolactone (SPL; 50 mg/kg/day) and sacrificed after 8, 16 and 24 weeks. Results Rats gradually developed proteinuria from 8 weeks after induction of diabetes. Immunostaining for Wilms' tumor-1 (WT1) and synaptopodin, markers of podocytes, was attenuated, whereas immunostaining for desmin, a marker of podocyte damage, and 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress, was up-regulated in the glomeruli of diabetic rats. Diabetic rats showed hypoaldosteronemia compared to the control, whereas SPL decreased proteinuria, ROS production and podocyte damage. To elucidate the paradox between hypoaldosteronemia and effect of SPL under hyperglycemia, the role of high glucose in MR activation and podocyte injury was explored. In cultured MR-expressing podocytes, high glucose significantly enhanced Sgk1 expression, activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and ROS production and induced podocyte apoptosis. All these effects were inhibited by SPL. Conclusion We conclude that hyperglycemia in diabetes, independent of plasma aldosterone concentration, induces podocyte injury through MR-mediated ROS production and leads to proteinuria. SPL inhibits hyperglycemia-induced podocyte injury by attenuating ROS production. |
| Databáze: | OpenAIRE |
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