RP105 protects against ischemic and septic acute kidney injury via suppressing TLR4/NF-κB signaling pathways

Zhu, Jiefu; Zhang, Yafei; Shi, Lang; Xia, Yao; Zha, Hongchu; Li, Huimin; Song, Zhixia

doi:10.1016/j.intimp.2022.108904

Cited by 14 publications

(5 citation statements)

References 24 publications

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“…For instance, in myocardial ischemia/reperfusion injury, RP105 plays a cardioprotective role by modulating both TLR2/TLR4 signaling pathways ( 32 ). A recent report implicated RP105 in preventing renal ischemic and septic acute kidney injury mediated by TLR4 signaling pathways ( 33 ). Cell-type-specific differences can also determine RP105 activity.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of inhibitory TLR4 homolog RP105 exacerbates fibrosis

Wang¹,

Bale²,

Yalavarthi³

et al. 2022

JCI Insight

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Activation of TLR4 by its cognate damage-associated molecular patterns (DAMPs) elicits potent profibrotic effects and myofibroblast activation in systemic sclerosis (SSc), while genetic targeting of TLR4 or its DAMPs in mice accelerates fibrosis resolution. To prevent aberrant DAMP/TLR4 activity, a variety of negative regulators evolved to dampen the magnitude and duration of the signaling. These include radioprotective 105 kDa (RP105), a transmembrane TLR4 homolog that competitively inhibits DAMP recognition of TLR4, blocking TLR4 signaling in immune cells. The role of RP105 in TLR4-dependent fibrotic responses in SSc is unknown. Using unbiased transcriptome analysis of skin biopsies, we found that levels of both TLR4 and its adaptor protein MD2 were elevated in SSc skin and significantly correlated with each other. Expression of RP105 was negatively associated with myofibroblast differentiation in SSc. Importantly, RP105-TLR4 association was reduced, whereas TLR4-TLR4 showed strong association in fibroblasts from patients with SSc, as evidenced by PLA assays. Moreover, RP105 adaptor MD1 expression was significantly reduced in SSc skin biopsies and explanted SSc skin fibroblasts. Exogenous RP105-MD1 abrogated, while loss of RP105 exaggerated, fibrotic cellular responses. Importantly, ablation of RP105 in mice was associated with augmented TLR4 signaling and aggravated skin fibrosis in complementary disease models. Thus, we believe RP105-MD1 to be a novel cell-intrinsic negative regulator of TLR4-MD2–driven sustained fibroblast activation, representing a critical regulatory network governing the fibrotic process. Impaired RP105 function in SSc might contribute to persistence of progression of the disease.

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Section: Discussionmentioning

confidence: 99%

Deficiency of inhibitory TLR4 homolog RP105 exacerbates fibrosis

Wang¹,

Bale²,

Yalavarthi³

et al. 2022

JCI Insight

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“…The recombinant lentiviral plasmids were verified by sequencing and co-transfected with pMD2G and pSPAX2 into BUMPT cells to produce recombinant lentiviral. Lentivirus infections were carried out as described previously [ 23 ]. Briefly, the cells were seeded in 24-well plates to achieve approximately 70–80% confluence at 24 h, and then the 10% DMEM medium was removed.…”

Section: Methodsmentioning

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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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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“…TLR4 is crucial for triggering inflammatory reactions, especially in sepsis‐, folic acid‐, and ischemia/reperfusion‐induced AKI 175–177 . There is no direct evidence of an interaction between Piezo1 and TLR4 in the kidney.…”

Section: Piezo1 and Kidney Diseasesmentioning

confidence: 99%

“…TLR4 is crucial for triggering inflammatory reactions, especially in sepsis-, folic acid-, and ischemia/reperfusioninduced AKI. [175][176][177] There is no direct evidence of an interaction between Piezo1 and TLR4 in the kidney. However, Geng et al demonstrated that bacterial infection or lipopolysaccharide stimulation triggers the assembly of Piezo1 and TLR4 complexes in macrophages and the remodeling of F-actin, thereby exerting anti-inflammatory and anti-bacterial activities and that this process was regulated by CaMKII-Mst1/2-Rac signaling pathway.…”

Section: Kidney Inflammationmentioning

confidence: 99%

Mechanosensing by Piezo1 and its implications in the kidney

Yuan,

Zhao,

Wang

et al. 2024

Acta Physiologica

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Piezo1 is an essential mechanosensitive transduction ion channel in mammals. Its unique structure makes it capable of converting mechanical cues into electrical and biological signals, modulating biological and (patho)physiological processes in a wide variety of cells. There is increasing evidence demonstrating that the piezo1 channel plays a vital role in renal physiology and disease conditions. This review summarizes the current evidence on the structure and properties of Piezo1, gating modulation, and pharmacological characteristics, with special focus on the distribution and (patho)physiological significance of Piezo1 in the kidney, which may provide insights into potential treatment targets for renal diseases involving this ion channel.

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RP105 protects against ischemic and septic acute kidney injury via suppressing TLR4/NF-κB signaling pathways

Cited by 14 publications

References 24 publications

Deficiency of inhibitory TLR4 homolog RP105 exacerbates fibrosis

Deficiency of inhibitory TLR4 homolog RP105 exacerbates fibrosis

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

Mechanosensing by Piezo1 and its implications in the kidney

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