Pioglitazone Improves Mitochondrial Function in the Remnant Kidney and Protects against Renal Fibrosis in 5/6 Nephrectomized Rats

Abstract

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.

Positron emission tomography imaging of renal mitochondria is a powerful tool in the study of acute and progressive kidney disease models

“…Decreased amounts of mitochondrial proteins (e.g., acyl-coenzyme A dehydrogenase medium chain, heat shock protein family A member 9, ATP synthase F1 subunit beta, NADH:ubiquinone oxidoreductase subunit B8, and mitochondrially encoded cytochrome c oxidase I), and mitochondrial DNA in the renal tissue of 5/6Nx rats were reported throughout the disease progression. 9,37 In this study, the renal uptake of 18 F-BCPP-BF had already started, albeit mildly, to decrease in the early phase of disease progression, then at the progression phase, the decrease was exacerbated along with the decline of the renal function. Mitochondrial proteins were remarkably decreased in the kidneys of 15-week-old 5/6 Nx rats.…”

“…One direct method is to measure the oxygen consumption rate of isolated mitochondria. [9][10][11] However, the complicated process of mitochondrial isolation may cause data variation. The mitochondrial morphology (e.g., fragmentation or hyperfusion) is a widely accepted indicator of their functional status.…”

Role of mitochondria and mitochondria‐targeted agents in non‐alcoholic fatty liver disease

“…Pioglitazone can inhibit pyruvate‐driven ATP synthesis and glucose production in isolated mitochondria from hepatocytes . Further, it can prevent the cytochrome C leakage, stabilize the mitochondrial membrane potential, maintain the ATP production, inhibit the ROS generation and activities the ETC complexes I and III . However, its role in NAFLD has not yet been evaluated.…”

Toxicity of Pioglitazone on Mitochondria Isolated from Brain and Heart: An Analysis for Probable Drug-Induced Neurotoxicity and Cardiotoxicity

“…Brain and heart tissues depend on mitochondria for their high energy consumption and maintenance of their normal function [15,16]. Research has shown that mitochondria are one of the targets of PPARγ agonists [3,17,18]. Mitochondrial dysfunction has been reported by exposure to TZDs.…”

“…Mitochondria as one of the important organelles in eukaryotic cells are involved in important physiological processes including the generation of free radicals, energy production and cell death [2,3,14,19,22]. Therefore, mitochondrial dysfunction can be dangerous for different cells and organs due to insufficient ATP generation and excessive level of ROS [18]. The in vitro cytotoxicity investigations can be helpful in providing mechanistic information, and this information can be useful in understanding the more detailed clinical observations [19].…”