CXC Chemokine Receptor 2 Accelerates Tubular Cell Senescence and Renal Fibrosis via β-Catenin-Induced Mitochondrial Dysfunction

Meng, Ping; Huang, Jiewu; Ling, Xian; Zhou, Shi‐Ping; Wei, Jingyan; Zhu, Mingyao; Miao, Jinhua; Sui, Weiwei; Li, Jiemei; Ye, Huiyun; Niu, Hongxin; Zhang, Yunfang; Zhou, Lili

doi:10.3389/fcell.2022.862675

Cited by 8 publications

(8 citation statements)

References 42 publications

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“…Analysis of existing single nuclear RNAseq of injured mouse kidneys indicates that Cxcl5 is highly expressed in different segments of nephron epithelial cells, while Cxcr2 is highly expressed in epithelial cells, immune cells and interstitial cells 90,91 . Inhibition of Cxcr2 protects against tubular cell senescence and renal fibrosis following unilateral ureteral obstruction (UUO) 92 , and reduces kidney injury associated with a reduction of inflammatory cytokines and neutrophils infiltration 93 . Intriguingly, it was shown that liver cysts of ADPKD patients secrete agonists of Cxcr2, which promote cell proliferation and cyst growth 94 .…”

Section: Discussionmentioning

confidence: 99%

Aberrant centrosome biogenesis disrupts nephron progenitor cell renewal and fate resulting in fibrocystic kidney disease

Cheng

Agwu

Shim

et al. 2023

Preprint

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Mutations that disrupt centrosome structure or function cause congenital kidney developmental defects and fibrocystic pathologies. Yet, it remains unclear how mutations in proteins essential for centrosome biogenesis impact embryonic kidney development. Here, we examined the consequences of conditional deletion of a ciliopathy gene, Cep120, in the two nephron progenitor niches of the embryonic kidney. Cep120 loss led to reduced abundance of both metanephric mesenchyme and ureteric bud progenitor populations. This was due to a combination of delayed mitosis, increased apoptosis, and premature differentiation of progenitor cells. These defects resulted in dysplastic kidneys at birth, which rapidly formed cysts, displayed increased interstitial fibrosis, and decline in filtration function. RNA sequencing of embryonic and postnatal kidneys from Cep120-null mice identified changes in pathways essential for branching morphogenesis, cystogenesis and fibrosis. Our study defines the cellular and developmental defects caused by centrosome dysfunction during kidney development, and identifies new therapeutic targets for renal centrosomopathies.

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Section: Discussionmentioning

confidence: 99%

Aberrant centrosome biogenesis disrupts nephron progenitor cell renewal and fate resulting in fibrocystic kidney disease

Cheng

Agwu

Shim

et al. 2023

Preprint

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“…Immunofluorescence staining was performed with routine protocol [ 72 ]. Frozen kidney sections (3 μm) were fixed with 4% paraformaldehyde.…”

Section: Methodsmentioning

confidence: 99%

Sirtuin 6 is a key contributor to gender differences in acute kidney injury

et al. 2023

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Acute kidney injury (AKI) is rapidly increasing nowadays and at a high risk to progress into chronic kidney disease (CKD). Of note, men are more susceptive to AKI, suggesting gender differences in AKI patients. However, the underlying mechanisms remain largely unclear. To test it, we adopted two experimental models of AKI, including ischemia/reperfusion injury and rhabdomyolysis, which were constructed in age-matched male and female mice. We found severe damages of tubular apoptosis, mitochondrial dysfunction, and loss of renal function showing in male mice, while female mice only had very mild injury. We further tested the expression of Sirtuins, and found that female mice could preserve more Sirtuin members’ expression in case of kidney damage. Among Sirtuin family, Sirtuin 6 was maximally preserved in injured kidney in female mice, suggesting its important role involved in the gender differences of AKI pathogenesis. We then found that knockdown of androgen receptor (AR) attenuated tubular damage, mitochondrial dysfunction and retarded the loss of renal function. Overexpression of Sirtuin 6 also showed similar results. Furthermore, in cultured tubular cells, dihydrotestosterone (DHT) decreased Sirtuin 6 expression and exacerbated cell apoptosis. Ectopic expression of Sirtuin 6 sufficiently inhibited DHT-induced cell apoptosis. Mechanically, we found AR inhibited Sirtuin 6, leading to the repression of binding of Sirtuin 6 with PGC-1α. This resulted in acetylation of PGC-1α and inhibition of its activity, further triggered the loss of mitochondrial homeostasis. Our results provided new insights to the underlying mechanisms of gender differences in AKI, suggesting Sirtuin 6 maybe a new therapeutic target for preventing AKI in male patients.

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“…TRPC6 channel also affects components of the innate immune response. It has been reported that TRPC6 channels regulate CXC chemokine receptor 2 (CXCR2)-related chemotaxis by mediating Ca 2+ influx ( Lindemann et al, 2013 ), promoting renal tubular cell senescence and renal fibrosis by inducing mitochondrial dysfunction ( Meng et al, 2022 ). Interestingly, Klotho, a single-channel type 1 transmembrane protein with anti-renal fibrotic effects, had no effect on obstruction-induced fibrosis in TRPC6 knockout mice, suggesting that the renal protective effect of Klotho in UUO is partly mediated through inhibition of TRPC6 ( Satoh et al, 2012 ; Wu et al, 2017b ).…”

Section: Ca 2+ Channelsmentioning

confidence: 99%

Ion channels as a therapeutic target for renal fibrosis

Yan

Fang

2022

Front. Physiol.

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Renal ion channel transport and electrolyte disturbances play an important role in the process of functional impairment and fibrosis in the kidney. It is well known that there are limited effective drugs for the treatment of renal fibrosis, and since a large number of ion channels are involved in the renal fibrosis process, understanding the mechanisms of ion channel transport and the complex network of signaling cascades between them is essential to identify potential therapeutic approaches to slow down renal fibrosis. This review summarizes the current work of ion channels in renal fibrosis. We pay close attention to the effect of cystic fibrosis transmembrane conductance regulator (CFTR), transmembrane Member 16A (TMEM16A) and other Cl− channel mediated signaling pathways and ion concentrations on fibrosis, as well as the various complex mechanisms for the action of Ca2+ handling channels including Ca2+-release-activated Ca2+ channel (CRAC), purinergic receptor, and transient receptor potential (TRP) channels. Furthermore, we also focus on the contribution of Na+ transport such as epithelial sodium channel (ENaC), Na+, K+-ATPase, Na+-H+ exchangers, and K+ channels like Ca2+-activated K+ channels, voltage-dependent K+ channel, ATP-sensitive K+ channels on renal fibrosis. Proposed potential therapeutic approaches through further dissection of these mechanisms may provide new therapeutic opportunities to reduce the burden of chronic kidney disease.

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CXC Chemokine Receptor 2 Accelerates Tubular Cell Senescence and Renal Fibrosis via β-Catenin-Induced Mitochondrial Dysfunction

Cited by 8 publications

References 42 publications

Aberrant centrosome biogenesis disrupts nephron progenitor cell renewal and fate resulting in fibrocystic kidney disease

Aberrant centrosome biogenesis disrupts nephron progenitor cell renewal and fate resulting in fibrocystic kidney disease

Sirtuin 6 is a key contributor to gender differences in acute kidney injury

Ion channels as a therapeutic target for renal fibrosis

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