Tubular TMEM16A promotes tubulointerstitial fibrosis by suppressing PGC-1α-mediated mitochondrial homeostasis in diabetic kidney disease

Ji, Jia-Ling; Li, Jun-Ying; Liang, Jian-Xiang; Zhou, Yan; Liu, Cong-Cong; Zhang, Yao; Zhang, Ai-Qing; Liu, Hong; Ma, Rui-Xia; Li, Zuo-Lin

doi:10.1007/s00018-023-05000-6

Cited by 6 publications

(1 citation statement)

References 32 publications

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“…Growing evidence has demonstrated that tubular epithelial cells change and become fibrogenic in response to hyperglycemia-induced injury. This results in tubulointerstitial fibrosis, which is one of the most prevalent pathological features of DKD ( Cui et al, 2022 ; Ji et al, 2023 ). Recent research has shown that methylation of the senescence-related gene p21 regulates metabolic memory and fibrosis in tubular epithelial cells in DKD ( Al-Dabet et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

The role of metabolic memory in diabetic kidney disease: identification of key genes and therapeutic targets

Yang,

Feng,

Shao

et al. 2024

Front. Pharmacol.

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Diabetic kidney disease (DKD) is characterized by complex pathogenesis and poor prognosis; therefore, an exploration of novel etiological factors may be beneficial. Despite glycemic control, the persistence of transient hyperglycemia still induces vascular complications due to metabolic memory. However, its contribution to DKD remains unclear. Using single-cell RNA sequencing data from the Gene Expression Omnibus (GEO) database, we clustered 12 cell types and employed enrichment analysis and a cell‒cell communication network. Fibrosis, a characteristic of DKD, was found to be associated with metabolic memory. To further identify genes related to metabolic memory and fibrosis in DKD, we combined the above datasets from humans with a rat renal fibrosis model and mouse models of metabolic memory. After overlapping, NDRG1, NR4A1, KCNC4 and ZFP36 were selected. Pharmacology analysis and molecular docking revealed that pioglitazone and resveratrol were possible agents affecting these hub genes. Based on the ex vivo results, NDRG1 was selected for further study. Knockdown of NDRG1 reduced TGF-β expression in human kidney-2 cells (HK-2 cells). Compared to that in patients who had diabetes for more than 10 years but not DKD, NDRG1 expression in blood samples was upregulated in DKD patients. In summary, NDRG1 is a key gene involved in regulating fibrosis in DKD from a metabolic memory perspective. Bioinformatics analysis combined with experimental validation provided reliable evidence for identifying metabolic memory in DKD patients.

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Section: Discussionmentioning

confidence: 99%