Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis

Livingston, Man J.; Shu, Shaoqun; Fan, Ying; Li, Ze; Jiao, Qiong; Yin, Xiao‐Ming; Venkatachalam, Manjeri A.; Dong, Zheng

doi:10.1080/15548627.2022.2072054

Cited by 54 publications

(22 citation statements)

References 70 publications

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“…HDAC6 has been reported to be involved in autophagy regulation in podocytes [ 28 ] and proximal tubular cells [ 29 ]. Atg7 and Beclin-1 are two conjugation system proteins in autophagosome formation [ 30 ]. IRI activation of autophagy manifested as the increased level of LC3 and beclin1 expression in tubular epithelial cells detected by IHC ( Figure 5 A,B).…”

Section: Resultsmentioning

confidence: 99%

“…ATG7 is an essential protein for the induction of autophagy, and the absence of ATG7 leads to a decrease in autophagosome formation [ 13 , 30 ]. To further define the role of TA and tubular cell autophagy in AKI, we established a conditional knockout mouse model, in which Atg7 was deleted specifically from renal tubules in kidneys ( Figure 8 A,B).…”

Section: Resultsmentioning

confidence: 99%

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HDAC6 Inhibition Alleviates Ischemia- and Cisplatin-Induced Acute Kidney Injury by Promoting Autophagy

Shi

Song

et al. 2022

Cells

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Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as α-tubulin. HDAC6 dysfunction is associated with several pathological conditions in renal disorders, including UUO-induced fibrotic kidneys and rhabdomyolysis-induced nephropathy. However, the role of HDAC6 in ischemic acute kidney injury (AKI) and the mechanism by which HDAC6 inhibition protects tubular cells after AKI remain unclear. In the present study, we observed that HDAC6 was markedly activated in kidneys subjected to ischemia- and cisplatin (cis)-induced AKI treatment. Pharmacological inhibition of HDAC6 alleviated renal impairment and renal tubular damage after ischemia and cisplatin treatment. HDAC6 dysfunction was associated with decreased acetylation of α-tubulin at the residue of lysine 40 and autophagy. HDAC6 inhibition preserved acetyl-α-tubulin-enhanced autophagy flux in AKI and cultured tubular cells. Genetic ablation of the renal tubular (RT) Atg7 gene or pharmacological inhibition of autophagy suppressed the protective effects of HDAC6. Taken together, our study indicates that HDAC6 contributes to ischemia- and cisplatin-induced AKI by inhibiting autophagy and the acetylation of α-tubulin. These results suggest that HDAC6 could be a potential target for ischemic and nephrotoxic AKI.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

HDAC6 Inhibition Alleviates Ischemia- and Cisplatin-Induced Acute Kidney Injury by Promoting Autophagy

Shi

Song

et al. 2022

Cells

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“…In KEGG analysis, the pathways of autophagy, FoxO, mTOR, MAPK and Ras signalling were highly enriched. Previously, studies have demonstrated that these pathways were closely associated with ECM ( 52 , 53 ). Dysregulation of autophagy under stress conditions plays a crucial role in progressive renal and hepatic fibrosis ( 54 , 55 ).…”

Section: Discussionmentioning

confidence: 99%

Expression profiles of tRNA‑derived fragments in high glucose‑treated tubular epithelial cells

Zheng

et al. 2022

Exp Ther Med

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Transfer RNA-derived fragments (tRFs), a novel class of small non-coding RNA produced by the cleavage of pre-and mature tRNAs, are involved in various diseases. Renal tubulointerstitial fibrosis is a common final pathway in diabetic nephropathy (DN) in which hyperglycemia-induced tubular extracellular matrix (ECM) accumulation serves a vital role. The present study aimed to detect and investigate the role of tRFs in the accumulation of tubular ECM. Differentially expressed tRFs were analysed with high-throughput sequencing in primary mouse tubular epithelial cells treated with high glucose (HG). The Gene Ontology (GO) was used to analyze the potential molecular functions of these differentially expressed tRFs, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the associated signaling pathways involved in these differentially expressed tRFs. tRF-1:30-Gln-CTG-4 was overexpressed using tRF-1:30-Gln-CTG-4 mimic, followed by HG treatment. A total of 554 distinct tRFs were detected and 64 differentially expressed tRFs (fold change >2; P<0.05) were identified in tubular epithelial cells following high glucose (HG) treatment, among which 27 were upregulated and 37 were downregulated. Ten selected tRFs with the greatest difference (fold change >2; P<0.05) were verified to be consistent with small RNA-sequencing data, of which tRF-1:30-Gln-CTG-4 showed the most pronounced difference in expression and was significantly decreased in response to HG. GO analysis indicated that the differentially expressed tRFs were associated with 'cellular process', 'biological regulation' and 'metabolic process'. An analysis of the KEGG database suggested that these differentially expressed tRFs were involved in 'autophagy' and signaling pathways for 'forkhead box O', 'the mammalian target of rapamycin' and 'mitogen-activated protein kinase'. Finally, the overexpression of tRF-1:30-Gln-CTG-4 ameliorated HG-induced ECM accumulation in tubular epithelial cells. Therefore, the present study demonstrated that there may be a significant association between tRFs and HG-induced ECM accumulation in tubular epithelial cells; these differentially expressed tRFs warrant further study to explore the pathogenesis of DN.

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“…in various renal cells (fibroblasts, tubular cells, glomerular mesangial cells and epithelial cells, etc.) ( Livingston et al, 2022 ), which was mainly associated with the activation of TGF-β/Smad and AGE-PAGE pathways ( De Vriese et al, 2003 ; Ma and Meng, 2019 ). In this study, RNA-seq ( Supplementary Table S2 ) and qRT-PCR ( Figure 8 ) results also demonstrated that mRNA levels of Tgfb1 and Col1a1 were significantly increased in both adenine and UUO models of RF, and immunohistochemical analysis ( Figure 2D ) showed that protein expression of TGF-β1 was significantly increased.…”

Section: Discussionmentioning

confidence: 99%

Identification of six hub genes and two key pathways in two rat renal fibrosis models based on bioinformatics and RNA-seq transcriptome analyses

Cai

Chen

Liu

et al. 2022

Front. Mol. Biosci.

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Renal fibrosis (RF) is the common pathological manifestation and central treatment target of multiple chronic kidney diseases with high morbidity and mortality. Currently, the molecular mechanisms underlying RF remain poorly understood, and exploration of RF-related hub targets and pathways is urgently needed. In this study, two classical RF rat models (adenine and UUO) were established and evaluated by HE, Masson and immunohistochemical staining. To clear molecular mechanisms of RF, differentially expressed genes (DEGs) were identified using RNA-Seq analysis, hub targets and pathways were screened by bioinformatics (functional enrichment analyses, PPI network, and co-expression analysis), the screening results were verified by qRT-PCR, and potential drugs of RF were predicted by network pharmacology and molecular docking. The results illustrated that renal structures were severely damaged and fibrotic in adenine- and UUO-induced models, as evidenced by collagen deposition, enhanced expressions of biomarkers (TGF-β1 and α-SMA), reduction of E-cadherin biomarker, and severe renal function changes (significantly decreased UTP, CREA, Ccr, and ALB levels and increased UUN and BUN levels), etc. 1189 and 1253 RF-related DEGs were screened in the adenine and UUO models, respectively. Two key pathways (AGE-RAGE and NOD-like receptor) and their hub targets (Tgfb1, Col1a1, Nlrc4, Casp4, Trpm2, and Il18) were identified by PPI networks, co-expressed relationships, and qRT-PCR verification. Furthermore, various reported herbal ingredients (curcumin, resveratrol, honokiol, etc.) were considered as important drug candidates due to the strong binding affinity with these hub targets. Overall, this study mainly identified two key RF-related pathways (AGE-RAGE and NOD-like receptor), screened hub targets (Tgfb1, Col1a1, Nlrc4, Casp4, Trpm2, and Il18) that involved inflammation, ECM formation, myofibroblasts generation, and pyroptosis, etc., and provided referable drug candidates (curcumin, resveratrol, honokiol, etc.) in basic research and clinical treatment of RF.

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Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis

Cited by 54 publications

References 70 publications

HDAC6 Inhibition Alleviates Ischemia- and Cisplatin-Induced Acute Kidney Injury by Promoting Autophagy

HDAC6 Inhibition Alleviates Ischemia- and Cisplatin-Induced Acute Kidney Injury by Promoting Autophagy

Expression profiles of tRNA‑derived fragments in high glucose‑treated tubular epithelial cells

Identification of six hub genes and two key pathways in two rat renal fibrosis models based on bioinformatics and RNA-seq transcriptome analyses

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