Abstract
Purpose. In this study, we investigated the effect of PGC1α activators on mitochondrial fusion, fission, and autophagic quality control in renal tubular cells in a diabetic environment in vivo and in vitro. We also examined whether the upregulation of PGC1α attenuates diabetic tubulopathy by normalizing mitochondrial homeostasis. Methods. HKC8 cells were subjected to high-glucose conditions (30 mM D-glucose). Diabetes was induced with streptozotocin (STZ, 50 mg/kg i.p. for 5 days) in male C57/BL6J mice. AICAR or metformin was used as a PGC1α activator. Results. Treatment with the PGC1α activators AICAR and metformin improved functional mitochondrial mass in HKC8 cells in high-glucose conditions. Moreover, in renal proximal tubular cells, increased PGC1α activity correlated with the reversal of changes in Drp1, Mfn1, and LC3-II protein expression in a high-glucose environment. Normalized mitochondrial life cycles resulted in low ROS production and reduced apoptosis. AICAR and metformin treatment effectively mitigated albuminuria and renal histopathology and decreased the expression of TGFβ1 and αSMA in the kidneys of diabetic mice. Conclusions. Our results demonstrate that increases in PGC1α activity improve diabetic tubulopathy by modulating mitochondrial dynamics and autophagy.
Highlights
The global prevalence of diabetes among adults over 18 years of age has rapidly risen from 4.7% in 1980 to 8.5% in 2014 [1]
We demonstrate that reduced PGC1α expression in renal proximal tubular cells is related to abnormal dynamics and quality control of mitochondria under highglucose conditions and that PGC1α activation attenuates the effect of high-glucose conditions on kidney tubules in vivo and in vitro
We studied the effect of a high-glucose environment on the expression of the key transcriptional coactivator of mitochondrial proteins, PGC1α, in human renal proximal tubular cells after treatment with 5 mM or 30 mM D-glucose for 24 h
Summary
The global prevalence of diabetes among adults over 18 years of age has rapidly risen from 4.7% in 1980 to 8.5% in 2014 [1]. DKD accounts for a significant increase in morbidity and mortality in patients with diabetes, and care for these patients is associated with substantial costs to society [3]. The roles of the glomerular filtration barrier in the development of albuminuria, which is a cardinal feature of DKD, are known, recent data have shown that only selective defects in tubular transport processes result in albuminuria or proteinuria [4]. It is clear that tubular epithelial cells under high-glucose conditions show elevated activation of proinflammatory and profibrotic signal transduction pathways, which contribute to progressive interstitial fibrosis [5]. Given that the extent of renal dysfunction correlates well with the degree of interstitial fibrosis [6], diabetic tubulopathy must be considered and explored as much as diabetic glomerulopathy in the pathogenesis of DKD
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