PYRUVATE KINASE M2 ACTIVATION MAINTAINS MITOCHONDRIAL METABOLISM BY REGULATING THE INTERACTION BETWEEN HIF-1α AND PGC-1α IN DIABETIC KIDNEY DISEASE.
Young Su Joo1, Jimin Park1, Bo Young Nam Gyuri Kim Jung Tak Park Tae-Hyun Yoo Shin-Wook Kang Seung Hyeok Han1 1Department of Internal Medicine, Institute of Kidney Disease Research, College of Medicine, Yonsei University, Seoul, Seoul, Republic of Korea
Abstract
Aim: To clarify mechanistic link between pyruvate kinase isoform M2 (PKM2) and HIF-1α-mediated PGC-1α suppression in animal model of diabetic kidney disease (DKD).
Backgrounds: Previous findings have indicated that PKM2 activation may protect kidney injury by improving mitochondrial dysfunction. However, the underlying molecular mechanisms are incompletely understood.
Methods: In an animal DKD study, db/db mice were intraperitoneally injected with TEPP-46, a PKM2 activator. In vitro, primary cultured renal tubular epithelial cells (RTECs) from C57BL/6 mice were treated with high glucose (HG) alone and HG+TEPP-46. The interactions between HIF-1α and PGC-1α were further investigated using HIF-1α overexpression and HIF-1α knockdown. PKM2 activity, energy metabolism, mitochondrial dysfunction, and cell injury markers were examined.
Results: In the kidney of db/db mice, diabetes resulted in decreased PKM2 activation, aberrant glycolysis, impaired fatty acid oxidation, and decreased mitochondrial mass, integrity, and function. These changes were accompanied by increased HIF-1α levels and decreased PGC-1α levels. In addition, increased fibrosis and apoptosis markers were observed in diabetic mice. The direct PKM2 activation by TEPP-46 treatment attenuated the dysregulated energy metabolism, mitochondrial dysfunction, and cell death. Similar alterations were also observed in HG-treated RTECs, which were restored by TEPP-46. Notably, a chromatin immunoprecipitation assay revealed that HIF-1α directly binds to the regulatory region of the Ppargc1a promoter and that this interaction is inversely dependent on PKM2 activation. A luciferase reporter assay showed that HIF-1α regulates the transcriptional activity of PGC-1α in a PKM2-dependent manner. Moreover, Hif1a overexpression suppressed PGC-1α and induced aberrant energy metabolism, mitochondrial dysfunction, and apoptosis. Conversely, these changes were reversed by HIF-1α knockdown.
Conclusion: PKM2 activation improves impaired mitochondrial metabolism and function by modulating HIF-1α and PGC-1α interactions in DKD.
Biography
Dr Young Su Joo, MD, PhD
Assistant Professor (Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea)