Advanced Glycation Endproducts Stimulate Renal Epithelial Cells to Release Chemokines That Recruit Macrophages, Leading to Renal Fibrosis

Sasai, Yosuke; Iwakawa, Kousei; Yanagida, Kanako; Shen, Yan; Hosono, Takashi; Ariga, Toshio; Seki, Taiichiro

doi:10.1271/bbb.120347

Cited by 16 publications

(12 citation statements)

References 31 publications

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“…To detect changing expression of MATE1/SLC47A1 in dose- and time-dependent manners, human proximal tubular epithelial cells were incubated with a-HSA or AGE-a-HSA. The dose dependency of the effects after a-HSA or AGE-a-HSA treatment was investigated according to previous report; 13 the cells were incubated with a-HSA or AGE-a-HSA (0, 1.25, 2.5, and 3.75 mg/mL) for 24 hours (n=6, at each groups). A serum-free proximal tubular epithelial cell growth medium was used as a control medium.…”

Section: Methodsmentioning

confidence: 99%

Significance of downregulation of renal organic cation transporter (SLC47A1) in cisplatin-induced proximal tubular injury

Mizuno¹,

Sato²,

Ishikawa³

et al. 2015

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Background/aimTo elucidate the mechanism responsible for developing acute kidney injury in patients with diabetes mellitus, we also evaluated the issue of whether advanced glycation endproducts (AGEs) influence the expressions of multi antimicrobial extrusion protein (MATE1/SLC47A1) in tubular cells.Materials and methodsTo detect changing expression of MATE1/SLC47A1 in dose- and time-dependent manners, human proximal tubular epithelial cells were incubated with AGE-aggregated-human serum albumin. As a function assay for MATE1/SLC47A1, human proximal tubular epithelial cells were incubated with cisplatin or carboplatin.ResultsOn incubation with AGEs, the expressions of MATE1/SLC47A1 were decreased in tubular cells. In addition, the toxicities of cisplatin were increased in tubular cells that had been pretreated with AGEs. However, the toxicities of carboplatin were smaller than that of cisplatin in proximal tubular epithelial cells.ConclusionThe expression of the MATE1/SLC47A1 is decreased by AGEs, which increases the risk for proximal tubular injury.

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Section: Methodsmentioning

confidence: 99%

Significance of downregulation of renal organic cation transporter (SLC47A1) in cisplatin-induced proximal tubular injury

Mizuno¹,

Sato²,

Ishikawa³

et al. 2015

OTT

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“…The expression of Tgm2 is increased by exposure to advanced glycation end products [ 32 ] and is suggested to induce renal fibrosis in the aging kidney [ 33 ]. The Jak2 /Stat signaling cascade is present in tubular epithelial and tubulointerstitial cells and is activated in various renal disease models [ 34 , 35 ].…”

Section: Resultsmentioning

confidence: 99%

TSS-Seq analysis of low pH-induced gene expression in intercalated cells in the renal collecting duct

et al. 2017

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Metabolic acidosis often results from chronic kidney disease; in turn, metabolic acidosis accelerates the progression of kidney injury. The mechanisms for how acidosis facilitates kidney injury are not fully understood. To investigate whether low pH directly affects the expression of genes controlling local homeostasis in renal tubules, we performed transcription start site sequencing (TSS-Seq) using IN-IC cells, a cell line derived from rat renal collecting duct intercalated cells, with acid loading for 24 h. Peak calling identified 651 up-regulated and 128 down-regulated TSSs at pH 7.0 compared with those at pH 7.4. Among them, 424 and 38 TSSs were ≥ 1.0 and ≤ -1.0 in Log2 fold change, which were annotated to 193 up-regulated and 34 down-regulated genes, respectively. We used gene ontology analysis and manual curation to profile the up-regulated genes. The analysis revealed that many up-regulated genes are involved in renal fibrosis, implying potential molecular mechanisms induced by metabolic acidosis. To verify the activity of the ubiquitin-proteasome system (UPS), a candidate pathway activated by acidosis, we examined the expression of proteins from cells treated with a proteasome inhibitor, MG132. The expression of ubiquitinated proteins was greater at pH 7.0 than at pH 7.4, suggesting that low pH activates the UPS. The in vivo study demonstrated that acid loading increased the expression of ubiquitin proteins in the collecting duct cells in mouse kidneys. Motif analysis revealed Egr1, the mRNA expression of which was increased at low pH, as a candidate factor that possibly stimulates gene expression in response to low pH. In conclusion, metabolic acidosis can facilitate renal injury and fibrosis during kidney disease by locally activating various pathways in the renal tubules.

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“…Maladaptive TECs can secrete CCL2 and CCL5 to recruit monocytes and macrophages 97 – 99 . Peripheral monocytes that are recruited can differentiate into macrophages once they arrive at the renal interstitium 98 .…”

Section: How Do Tecs Interact With Other Cell Types In the Interstitimentioning

confidence: 99%

Renal tubular epithelial cells: the neglected mediator of tubulointerstitial fibrosis after injury

2018

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Renal fibrosis, especially tubulointerstitial fibrosis, is the inevitable outcome of all progressive chronic kidney diseases (CKDs) and exerts a great health burden worldwide. For a long time, interests in renal fibrosis have been concentrated on fibroblasts and myofibroblasts. However, in recent years, growing numbers of studies have focused on the role of tubular epithelial cells (TECs). TECs, rather than a victim or bystander, are probably a neglected mediator in renal fibrosis, responding to a variety of injuries. The maladaptive repair mechanisms of TECs may be the key point in this process. In this review, we will focus on the role of TECs in tubulointerstitial fibrosis. We will follow the fate of a tubular cell and depict the intracellular changes after injury. We will then discuss how the repair mechanism of tubular cells becomes maladaptive, and we will finally discuss the intercellular crosstalk in the interstitium that ultimately proceeds tubulointerstitial fibrosis.

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Advanced Glycation Endproducts Stimulate Renal Epithelial Cells to Release Chemokines That Recruit Macrophages, Leading to Renal Fibrosis

Cited by 16 publications

References 31 publications

Significance of downregulation of renal organic cation transporter (SLC47A1) in cisplatin-induced proximal tubular injury

Significance of downregulation of renal organic cation transporter (SLC47A1) in cisplatin-induced proximal tubular injury

TSS-Seq analysis of low pH-induced gene expression in intercalated cells in the renal collecting duct

Renal tubular epithelial cells: the neglected mediator of tubulointerstitial fibrosis after injury

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