Thioredoxin interacting protein (TXNIP) regulates tubular autophagy and mitophagy in diabetic nephropathy through the mTOR signaling pathway

Abstract

Hyperglycemia upregulates thioredoxin interacting protein (TXNIP) expression, which in turn induces ROS production, inflammatory and fibrotic responses in the diabetic kidney. Dysregulation of autophagy contributes to the development of diabetic nephropathy. However, the interaction of TXNIP with autophagy/mitophagy in diabetic nephropathy is unknown. In this study, streptozotocin-induced diabetic rats were given TXNIP DNAzyme or scrambled DNAzyme for 12 weeks respectively. Fibrotic markers, mitochondrial function and mitochondrial reactive oxygen species (mtROS) were assessed in kidneys. Tubular autophagy and mitophagy were determined in kidneys from both human and rats with diabetic nephropathy. TXNIP and autophagic signaling molecules were examined. TXNIP DNAzyme dramatically attenuated extracellular matrix deposition in the diabetic kidneys compared to the control DNAzyme. Accumulation of autophagosomes and reduced autophagic clearance were shown in tubular cells of human diabetic compared to non-diabetic kidneys, which was reversed by TXNIP DNAzyme. High glucose induced mitochondrial dysfunction and mtROS production, and inhibited mitophagy in proximal tubular cells, which was reversed by TXNIP siRNA. TXNIP inhibition suppressed diabetes-induced BNIP3 expression and activation of the mTOR signaling pathway. Collectively, hyperglycemia-induced TXNIP contributes to the dysregulation of tubular autophagy and mitophagy in diabetic nephropathy through activation of the mTOR signaling pathway.

The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1

“…4). These results are consistent with those of previous reports involving type I diabetic mice [3], [13] and are also consistent with previous observations regarding diabetic hearts and skeletal muscles. [48], [49] MitoQ dramatically reversed mitophagy by up-regulating PINK and Parkin expression (Fig.…”

“…Mitochondrial ATP activity was assayed using a ATP bioluminescence assay kit (Roche Diagnostics, Switzerland), according to the manufacturer's instructions. [13].…”

“…[3] Huang CH et al demonstrated that mitophagy inhibition was associated with tubular damage via the thioredoxin interacting protein (TXNIP)/mTOR/BNIP3 signaling pathway in diabetic mice. [13] Therefore, the present study examined the maintenance of mitochondrial quality control via mitophagy using a pharmacological method to decrease mitochondrial oxidative damage and protect against tubular damage in a hyperglycemic state.…”

Thioredoxin‐interacting protein induced α‐synuclein accumulation via inhibition of autophagic flux: Implications for Parkinson's disease

“…These findings point out that TXNIP may act as a scaffolding protein in signaling complex independent of the redox regulation . A few studies reported the impact of TXNIP on autophagy . Xin‐Ming Chen reported that TXNIP mediates dysfunction of tubular autophagy in diabetic kidneys through inhibition of autophagic flux .…”

Enhancement of high glucose‐induced PINK1 expression by melatonin stimulates neuronal cell survival: Involvement of MT2/Akt/NF‐κB pathway

“…In addition, previous researchers have reported that oxidative stress induced by hyperglycemia is an essential pathogenic factor contributing to several DM‐associated complications . Recently, several researchers reported a relationship between mitophagy‐regulated oxidative stress and the pathogenesis of diabetic heart and diabetic neuropathy, indicating that the interest of researchers in the protective action of mitophagy in DM patients has increased . It has been shown that PTEN‐induced putative kinase 1 (PINK1), Bcl2/adenovirus E1B 19 kDa protein‐interacting protein 3 (BNIP3), and NIX are major mitophagy regulators that can trigger mitophagy under oxidative and metabolic stress conditions .…”