Dataset Information

Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis.

ABSTRACT: Acute kidney injury (AKI) is a disease with mitochondrial dysfunction and a newly established risk factor for the development of chronic kidney disease (CKD) and fibrosis. We examined mitochondrial homeostasis in the folic acid (FA)-induced AKI model that develops early fibrosis over a rapid time course. Mice given a single dose of FA had elevated serum creatinine (3-fold) and urine glucose (2.2-fold) 1 and 2 d after injection that resolved by 4d. In contrast, peroxisome proliferator gamma coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM), critical transcriptional regulators of mitochondrial biogenesis (MB), were down-regulated ∼80% 1d after FA injection and remained depressed through 14 d. Multiple electron transport chain and ATP synthesis genes were also down-regulated from 1 to 14 d after FA, including NADH dehydrogenase (ubiquinone) 1 beta subcomplex 8 (NDUFβ8), ATP synthase subunit β (ATPS-β), and cytochrome C oxidase subunit I (COXI). Mitochondrial DNA copy number was reduced ∼50% from 2 to 14 d after FA injection. Protein levels of early fibrosis markers α-smooth muscle actin and transforming growth factor β1 were elevated at 6 and 14 d after FA. Picrosirius red staining and collagen 1A2 (COL1A2) IHC revealed staining for mature collagen deposition at 14 d. We propose that mitochondrial dysfunction induced by AKI is a persistent cellular injury that promotes progression to fibrosis and CKD, and that this model can be used to test mitochondrial therapeutics that limit progression to fibrosis and CKD.

SUBMITTER: Stallons LJ

PROVIDER: S-EPMC3987699 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis.

Stallons L Jay LJ Whitaker Ryan M RM Schnellmann Rick G RG

Toxicology letters 20131122 3

Acute kidney injury (AKI) is a disease with mitochondrial dysfunction and a newly established risk factor for the development of chronic kidney disease (CKD) and fibrosis. We examined mitochondrial homeostasis in the folic acid (FA)-induced AKI model that develops early fibrosis over a rapid time course. Mice given a single dose of FA had elevated serum creatinine (3-fold) and urine glucose (2.2-fold) 1 and 2 d after injection that resolved by 4d. In contrast, peroxisome proliferator gamma coact ...[more]

PMID: 24275386

Similar Datasets

Project description:Acute kidney injury (AKI) is defined by a significant reduction in renal function, which subsequently impairs coagulation and activates the inflammatory immune response, ultimately resulting in damage to renal tubular epithelial cells (TECs). Platelets are crucial in mediating both inflammatory and coagulation processes. While it is established that platelet activation contributes to the progression of AKI, the precise mechanisms underlying this relationship remain largely unclear. We investigated platelet function in folic acid-induced acute kidney injury (FA-AKI) and examined the effects of galectin-3, a protein derived from renal tubular epithelial cells (TECs), on its interaction with platelet glycoprotein VI (GPVI). This interaction was assessed through the analysis of monocyte migration, macrophage polarization, and the generation of monocyte-platelet aggregation. Additionally, we utilized platelet GPVI-specific knockout mice in conjunction with TD139, a small-molecule inhibitor of galectin-3, to explore the effects of inhibiting the galectin-3-GPVI interaction on FA-AKI. In the current study, we observed that mouse platelets displayed hyperactivity in the context of functional acute kidney injury (FA-AKI). This hyperactivity was linked to the interaction between galectin-3, which is derived from damaged renal tubular epithelial cells (TECs), and the glycoprotein VI (GPVI) on platelets. Our findings indicated a heightened interaction between activated platelets and monocytes, along with an increase in monocyte-platelet aggregation (MPA) within the circulation. The increased infiltration of monocytes and platelets in renal tissue was further validated through CD41 and CD68 immunofluorescence techniques. Additionally, the interaction between galectin-3 and platelet GPVI was shown to facilitate monocyte migration, promote M1-type macrophage polarization, and enhance phagocytic activity. The galectin-3 inhibitor TD139 significantly suppressed monocyte-platelet aggregation (MPA), reduced inflammatory responses, and extended the survival of mice with acute kidney injury (AKI). These findings suggest that galectin-3, which is released from damaged cells during acute kidney injury (AKI), exacerbates renal inflammation and tissue damage by activating platelets through glycoprotein VI (GPVI). This activation enhances interactions between monocytes and platelets, ultimately leading to the formation of monocyte-platelet aggregates (MPA) and the polarization of M1 macrophages.

Dataset Information

Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis.

Publications

Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets