Increased long noncoding RNA maternally expressed gene 3 contributes to podocyte injury induced by high glucose through regulation of mitochondrial fission

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.

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

“…Noncoding RNAs are involved in the regulation of various mitochondrial pathways in DN ( 102 ). For example, miRNA-21 is downregulated in animal models of DN and CKD patients and can suppress the expression of PPAR-α, thereby regulating fatty acid β-oxidation ( 103 ).…”

“…Along with regulation of mitochondrial metabolism, lncRNAs have been identified which can regulate mitochondrial dynamics. For example, the lncRNA “Meg3” is increased in podocytes in diabetic conditions and correlates with an excessive mitochondrial fission and podocyte injury in DN ( 102 ).…”

Genistein Mitigates High Glucose-Induced Podocyte Adhesion Injury by Modulating Autophagy via Mtor Signal

“…The podocyte adhesion injury may occur in the early stage of DKD and play a key role in the progression of DKD (30). Integrin β1-MF is the main receptor mediating podocytes adhesion to GBM, which is essential to maintain the adhesion ability of cells (31,32).…”

Regulatory Role of Long Non-Coding RNA “Maternally-Expressed Gene-3” in Diabetic Nephropathy through Targeting microRNA-21 and Transforming Growth Factor-Beta

“…They play vital roles in different physiological processes. In addition, lncRNAs may be involved in the pathogenesis of many diseases through their sponging effect on miRNAs, according to the competing endogenous RNA (ceRNA) hypothesis [12]. Although the ceRNAs are the most recently discovered entrants in the different mechanisms of miRNA mediated gene regulation, we need more studies to fully understand their mechanisms of action [13].…”