Pioglitazone Improves Mitochondrial Function in the Remnant Kidney and Protects against Renal Fibrosis in 5/6 Nephrectomized Rats
Pioglitazone is a type of peroxisome proliferator-activated receptor γ (PPARγ) agonist and has been demonstrated to be effective in chronic kidney diseases (CKD) treatment. However, the underlying mechanism involved in the renoprotection of pioglitazone has not been fully revealed. In the present st...
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2017-08-01
|
Series: | Frontiers in Pharmacology |
Subjects: | |
Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2017.00545/full |
id |
doaj-92e439ad4fba45beb548836ee85e9434 |
---|---|
record_format |
Article |
spelling |
doaj-92e439ad4fba45beb548836ee85e94342020-11-24T22:39:50ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122017-08-01810.3389/fphar.2017.00545284480Pioglitazone Improves Mitochondrial Function in the Remnant Kidney and Protects against Renal Fibrosis in 5/6 Nephrectomized RatsLi Sun0Quan Yuan1Tianhua Xu2Li Yao3Jiangmin Feng4Jianfei Ma5Lining Wang6Changlong Lu7Danan Wang8Department of Nephrology, The First Affiliated Hospital of China Medical UniversityShenyang, ChinaDepartment of Orthopedic Surgery, Shengjing Hospital of China Medical UniversityShenyang, ChinaDepartment of Nephrology, The First Affiliated Hospital of China Medical UniversityShenyang, ChinaDepartment of Nephrology, The First Affiliated Hospital of China Medical UniversityShenyang, ChinaDepartment of Nephrology, The First Affiliated Hospital of China Medical UniversityShenyang, ChinaDepartment of Nephrology, The First Affiliated Hospital of China Medical UniversityShenyang, ChinaDepartment of Nephrology, The First Affiliated Hospital of China Medical UniversityShenyang, ChinaDepartment of Immunology, China Medical UniversityShenyang, ChinaDepartment of Immunology, China Medical UniversityShenyang, ChinaPioglitazone is a type of peroxisome proliferator-activated receptor γ (PPARγ) agonist and has been demonstrated to be effective in chronic kidney diseases (CKD) treatment. However, the underlying mechanism involved in the renoprotection of pioglitazone has not been fully revealed. In the present study, the renoprotective mechanism of pioglitazone was investigated in 5/6 nephrectomized (Nx) rats and TGF-β1-exposed HK-2 cells. Pioglitazone attenuated renal injury and improved renal function, as examined by 24 h urinary protein, blood urea nitrogen and plasma creatinine in Nx rats. Renal fibrosis and enhanced expressions of profibrotic proteins TGF-β1, fibronectin and collagen I caused by Nx were significantly alleviated by pioglitazone. In addition, pioglitazone protected mitochondrial functions by stabilizing the mitochondrial membrane potential, inhibiting ROS generation, maintaining ATP production and the activities of complexes I and III, and preventing cytochrome C leakage from mitochondria. Pioglitazone also upregulated the expression levels of ATP synthase β, COX I and NDUFB8, which were downregulated in the kidney of Nx rats and TGF-β1-exposed HK-2 cells. Furthermore, pioglitazone increased fusion proteins Opa-1 and Mfn2 expressions and decreased fission protein Drp1 expression. The results imply that pioglitazone may exert the renoprotective effects through modulating mitochondrial electron transport chain and mitochondrial dynamics in CKD. Finally, these recoveries were completely or partly inhibited by GW9662, which suggests that these effects at least partly PPARγ dependent. This study provides evidence for the pharmacological mechanism of pioglitazone in the treatment of CKD.http://journal.frontiersin.org/article/10.3389/fphar.2017.00545/fullchronic kidney diseasesperoxisome proliferator-activated receptor γpioglitazonefibrosismitochondrial dysfunction |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Li Sun Quan Yuan Tianhua Xu Li Yao Jiangmin Feng Jianfei Ma Lining Wang Changlong Lu Danan Wang |
spellingShingle |
Li Sun Quan Yuan Tianhua Xu Li Yao Jiangmin Feng Jianfei Ma Lining Wang Changlong Lu Danan Wang Pioglitazone Improves Mitochondrial Function in the Remnant Kidney and Protects against Renal Fibrosis in 5/6 Nephrectomized Rats Frontiers in Pharmacology chronic kidney diseases peroxisome proliferator-activated receptor γ pioglitazone fibrosis mitochondrial dysfunction |
author_facet |
Li Sun Quan Yuan Tianhua Xu Li Yao Jiangmin Feng Jianfei Ma Lining Wang Changlong Lu Danan Wang |
author_sort |
Li Sun |
title |
Pioglitazone Improves Mitochondrial Function in the Remnant Kidney and Protects against Renal Fibrosis in 5/6 Nephrectomized Rats |
title_short |
Pioglitazone Improves Mitochondrial Function in the Remnant Kidney and Protects against Renal Fibrosis in 5/6 Nephrectomized Rats |
title_full |
Pioglitazone Improves Mitochondrial Function in the Remnant Kidney and Protects against Renal Fibrosis in 5/6 Nephrectomized Rats |
title_fullStr |
Pioglitazone Improves Mitochondrial Function in the Remnant Kidney and Protects against Renal Fibrosis in 5/6 Nephrectomized Rats |
title_full_unstemmed |
Pioglitazone Improves Mitochondrial Function in the Remnant Kidney and Protects against Renal Fibrosis in 5/6 Nephrectomized Rats |
title_sort |
pioglitazone improves mitochondrial function in the remnant kidney and protects against renal fibrosis in 5/6 nephrectomized rats |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2017-08-01 |
description |
Pioglitazone is a type of peroxisome proliferator-activated receptor γ (PPARγ) agonist and has been demonstrated to be effective in chronic kidney diseases (CKD) treatment. However, the underlying mechanism involved in the renoprotection of pioglitazone has not been fully revealed. In the present study, the renoprotective mechanism of pioglitazone was investigated in 5/6 nephrectomized (Nx) rats and TGF-β1-exposed HK-2 cells. Pioglitazone attenuated renal injury and improved renal function, as examined by 24 h urinary protein, blood urea nitrogen and plasma creatinine in Nx rats. Renal fibrosis and enhanced expressions of profibrotic proteins TGF-β1, fibronectin and collagen I caused by Nx were significantly alleviated by pioglitazone. In addition, pioglitazone protected mitochondrial functions by stabilizing the mitochondrial membrane potential, inhibiting ROS generation, maintaining ATP production and the activities of complexes I and III, and preventing cytochrome C leakage from mitochondria. Pioglitazone also upregulated the expression levels of ATP synthase β, COX I and NDUFB8, which were downregulated in the kidney of Nx rats and TGF-β1-exposed HK-2 cells. Furthermore, pioglitazone increased fusion proteins Opa-1 and Mfn2 expressions and decreased fission protein Drp1 expression. The results imply that pioglitazone may exert the renoprotective effects through modulating mitochondrial electron transport chain and mitochondrial dynamics in CKD. Finally, these recoveries were completely or partly inhibited by GW9662, which suggests that these effects at least partly PPARγ dependent. This study provides evidence for the pharmacological mechanism of pioglitazone in the treatment of CKD. |
topic |
chronic kidney diseases peroxisome proliferator-activated receptor γ pioglitazone fibrosis mitochondrial dysfunction |
url |
http://journal.frontiersin.org/article/10.3389/fphar.2017.00545/full |
work_keys_str_mv |
AT lisun pioglitazoneimprovesmitochondrialfunctionintheremnantkidneyandprotectsagainstrenalfibrosisin56nephrectomizedrats AT quanyuan pioglitazoneimprovesmitochondrialfunctionintheremnantkidneyandprotectsagainstrenalfibrosisin56nephrectomizedrats AT tianhuaxu pioglitazoneimprovesmitochondrialfunctionintheremnantkidneyandprotectsagainstrenalfibrosisin56nephrectomizedrats AT liyao pioglitazoneimprovesmitochondrialfunctionintheremnantkidneyandprotectsagainstrenalfibrosisin56nephrectomizedrats AT jiangminfeng pioglitazoneimprovesmitochondrialfunctionintheremnantkidneyandprotectsagainstrenalfibrosisin56nephrectomizedrats AT jianfeima pioglitazoneimprovesmitochondrialfunctionintheremnantkidneyandprotectsagainstrenalfibrosisin56nephrectomizedrats AT liningwang pioglitazoneimprovesmitochondrialfunctionintheremnantkidneyandprotectsagainstrenalfibrosisin56nephrectomizedrats AT changlonglu pioglitazoneimprovesmitochondrialfunctionintheremnantkidneyandprotectsagainstrenalfibrosisin56nephrectomizedrats AT dananwang pioglitazoneimprovesmitochondrialfunctionintheremnantkidneyandprotectsagainstrenalfibrosisin56nephrectomizedrats |
_version_ |
1725707426000273408 |