Abstract
Excessive mitochondrial fission plays a key role in podocyte injury in diabetic kidney disease (DKD), and long noncoding RNAs (lncRNAs) are important in the development and progression of DKD. However, lncRNA regulation of mitochondrial fission in podocytes is poorly understood. Here, we studied lncRNA maternally expressed gene 3 (Meg3) in mitochondrial fission in vivo and in vitro using human podocytes and Meg3 podocyte-specific knockdown mice. Expression of lncRNA Meg3 in STZ-induced diabetic mice was higher, and correlated with the number of podocytes. Excessive mitochondrial fission of podocytes and renal histopathological and physiological parameters were improved in podocyte-specific Meg3 knockdown diabetic mice. Elongated mitochondria with attenuated podocyte damage, as well as mitochondrial translocation of dynamin-related protein 1 (Drp1), were decreased in Meg3 knockout podocytes. By contrast, increased fragmented mitochondria, podocyte injury, and Drp1 expression and phosphorylation were observed in lncRNA Meg3-overexpressing podocytes. Treatment with Mdivi1 significantly blunted more fragmented mitochondria and reduced podocyte injury in lncRNA Meg3-overexpressing podocytes. Finally, fragmented mitochondria and Drp1 mitochondrial translocation induced by high glucose were reduced following treatment with Mdivi1. Our data show that expression of Meg3 in podocytes in both human cells and diabetic mice was higher, which regulates mitochondrial fission and contributes to podocyte injury through increased Drp1 and its translocation to mitochondria.
Highlights
The prevalence of diabetes mellitus is increasing every year in China, and is currently estimated at 11.6%1
Results long noncoding RNAs (lncRNAs) Meg[3] expression is enhanced in human podocytes cultured with high glucose and podocytes of STZ-induced mice A lncRNA array was used to identify lncRNAs implicated in the regulation of human podocytes with high glucose (HG)
This study identified novel correlations between lncRNA Meg[3] expression and podocyte injury, and showed the importance of Meg[3] in mediating excessive mitochondrial fission in the development of diabetic kidney disease (DKD)
Summary
The prevalence of diabetes mellitus is increasing every year in China, and is currently estimated at 11.6%1. 30–40% of patients develop diabetic kidney disease (DKD)[2]. Most patients eventually progress to Podocyte damage is the primary pathological change evident in DKD5. Loss of >20% of podocytes results in irreversible glomerular damage that has been shown to progress to renal failure in animals[6,7]. Sufficient energy supply from mitochondria is crucial for podocytes to maintain their filter barrier, and insufficient energy due to mitochondrial damage results in the destruction of Official journal of the Cell Death Differentiation Association. Excessive mitochondrial fission (fragments) has been shown to contribute to the development and progression of DKD12. Wang et al.[13] provided the first evidence that excessive mitochondrial fission was a core feature of mitochondrial dysfunction in podocytes in DKD
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