Unresolved inflammation can lead to tissue fibrosis and impaired organ function. Macrophage–myofibroblast transition (MMT) is one newly identified mechanism by which ongoing chronic inflammation ...causes progressive fibrosis in different forms of kidney disease. However, the mechanisms underlying MMT are still largely unknown. Here, we discovered a brain-specific homeobox/POU domain protein Pou4f1 (Brn3a) as a specific regulator of MMT. Interestingly, we found that Pou4f1 is highly expressed by macrophages undergoing MMT in sites of fibrosis in human and experimental kidney disease, identified by coexpression of the myofibroblast marker, α-SMA. Unexpectedly, Pou4f1 expression peaked in the early stage in renal fibrogenesis in vivo and during MMT of bone marrow-derived macrophages (BMDMs) in vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assay identified that Pou4f1 is a Smad3 target and the key downstream regulator of MMT, while microarray analysis defined a Pou4f1-dependent fibrogenic gene network for promoting TGF-β1/Smad3-driven MMT in BMDMs at the transcriptional level. More importantly, using two mouse models of progressive renal interstitial fibrosis featuring the MMT process, we demonstrated that adoptive transfer of TGF-β1-stimulated BMDMs restored both MMT and renal fibrosis in macrophage-depleted mice, which was prevented by silencing Pou4f1 in transferred BMDMs. These findings establish a role for Pou4f1 in MMT and renal fibrosis and suggest that Pou4f1 may be a therapeutic target for chronic kidney disease with progressive renal fibrosis.
Clopidogrel, a P2Y12 inhibitor, is a novel anti-fibrosis agent for chronic kidney disease (CKD), but its mechanisms remain unclear, which we investigated by silencing P2Y12 or treating unilateral ...ureteral obstruction (UUO) in LysM-Cre/Rosa Tomato mice with clopidogrel in vivo and in vitro. We found that P2Y12 was significantly increased and correlated with progressive renal fibrosis in CKD patients and UUO mice. Phenotypically, up to 82% of P2Y12-expressing cells within the fibrosing kidney were of macrophage origin, identified by co-expressing CD68/F4/80 antigens or a macrophage-lineage-tracing marker Tomato. Unexpectedly, more than 90% of P2Y12-expressing macrophages were undergoing macrophage-to-myofibroblast transition (MMT) by co-expressing alpha smooth muscle actin (α-SMA), which was also confirmed by single-cell RNA sequencing. Functionally, clopidogrel improved the decline rate of the estimated glomerular filtration rate (eGFR) in patients with CKD and significantly inhibited renal fibrosis in UUO mice. Mechanistically, P2Y12 expression was induced by transforming growth factor β1 (TGF-β1) and promoted MMT via the Smad3-dependent mechanism. Thus, silencing or pharmacological inhibition of P2Y12 was capable of inhibiting TGF-β/Smad3-mediated MMT and progressive renal fibrosis in vivo and in vitro. In conclusion, P2Y12 is highly expressed by macrophages in fibrosing kidneys and mediates renal fibrosis by promoting MMT via TGF-β/Smad3 signaling. Thus, P2Y12 inhibitor maybe a novel and effective anti-fibrosis agent for CKD.
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P2Y12 is highly expressed by macrophages in fibrosing kidneys and mediates renal fibrosis by promoting MMT via TGF-β/Smad3 signaling. Thus, a P2Y12 inhibitor may be a novel and effective anti-fibrosis agent for CKD.
Acute kidney injury (AKI) is a common kidney disease with a high risk of death and can develop into chronic kidney disease (CKD) and renal failure eventually. Curcumin, an herbal supplement, has been ...reported exhibiting a renoprotective role in AKI. However, the underlying mechanism is largely unclear.
Recent research showed that Mincle (Macrophage-inducible C-type lectin) maintained M1 macrophage polarization, which plays a key role in kidney injury of AKI through up-regulating the expression and secretion of inflammatory cytokines. Here, we investigated the effects of Curcumin on Mincle expression and macrophage polarization in vitro using lipopolysaccharide (LPS) induced macrophage inflammatory cell model and in vivo using a cisplatin induced murine AKI (cis-AKI) model.
Cell activation, inflammatory cytokines expression and secretion, protein levels, macrophage polarization and renal pathology were analyzed.
Our results showed that Curcumin markedly reduced the mRNA expression and secretion of IL-1β, IL-6, TNFα and MCP-1 in LPS stimulated RAW264.7 cell and the supernatant. The same results were found in Curcumin treated cis-AKI kidney and blood. The data also demonstrated that Curcumin remarkably down-regulated mRNA expression and protein level of Mincle in cis-AKI kidney and also reduced expression of iNOS (M1 macrophage marker) as well as inhibited the activation of Syk and NF-kB. Interestingly, although Mincle deletion in RAW264.7 cell largely decreased the LPS-induced protein level of iNOS, Curcumin cannot further reduce expression of iNOS without Mincle, indicating that Curcumin inhibits M1 macrophage with a Mincle-dependent pattern. Furthermore, flow cytometry results showed that Curcumin significantly decreased the iNOS positive macrophages and increased the CD206 (M2 macrophage marker) positive macrophages in vivo and in vitro.
Our findings prove that Curcumin protects kidney from cisplatin induced AKI through inhibiting Mincle maintained M1 macrophage phenotype, that may provide a specific renoprotection mechanism for Curcumin to develop it as a new therapeutic candidate for AKI.
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Renal fibrosis is a common fate of chronic kidney diseases. Emerging studies suggest that unsolved inflammation will progressively transit into tissue fibrosis that finally results in an irreversible ...end-stage renal disease (ESRD). Renal inflammation recruits and activates immunocytes, which largely promotes tissue scarring of the diseased kidney. Importantly, studies have suggested a crucial role of innate immunity in the pathologic basis of kidney diseases. This review provides an update of both clinical and experimental information, focused on how innate immune signaling contributes to renal fibrogenesis. A better understanding of the underlying mechanisms may uncover a novel therapeutic strategy for ESRD.
Diverse Role of TGF-β in Kidney Disease Gu, Yue-Yu; Liu, Xu-Sheng; Huang, Xiao-Ru ...
Frontiers in cell and developmental biology,
02/2020, Letnik:
8
Journal Article
Recenzirano
Odprti dostop
Inflammation and fibrosis are two pathological features of chronic kidney disease (CKD). Transforming growth factor-β (TGF-β) has been long considered as a key mediator of renal fibrosis. In ...addition, TGF-β also acts as a potent anti-inflammatory cytokine that negatively regulates renal inflammation. Thus, blockade of TGF-β inhibits renal fibrosis while promoting inflammation, revealing a diverse role for TGF-β in CKD. It is now well documented that TGF-β1 activates its downstream signaling molecules such as Smad3 and Smad3-dependent non-coding RNAs to transcriptionally and differentially regulate renal inflammation and fibrosis, which is negatively regulated by Smad7. Therefore, treatments by rebalancing Smad3/Smad7 signaling or by specifically targeting Smad3-dependent non-coding RNAs that regulate renal fibrosis or inflammation could be a better therapeutic approach. In this review, the paradoxical functions and underlying mechanisms by which TGF-β1 regulates in renal inflammation and fibrosis are discussed and novel therapeutic strategies for kidney disease by targeting downstream TGF-β/Smad signaling and transcriptomes are highlighted.
Two suites of granitoids, the Late Jurassic (158 ± 3 Ma) Linglong suite and the Early Cretaceous (130–126 Ma) Guojialing suite, crop out in the northwestern Jiaodong Peninsula, eastern China. The ...Linglong suite is a monzogranite, comprising alkali feldspar, plagioclase, quartz and Fe-rich biotite. The Guojialing suite includes at least five plutonic bodies of both granodiorite and monzo-granite. The rocks are composed of plagioclase, alkali feldspar, quartz, Mg-rich amphibole and Mg-rich biotite. Both the Linglong and Guojialing suites have adakitic affinity. They are enriched in LREE with high La/Yb ratios and show positive Eu anomalies. The rocks are also enriched in LILE and depleted in HFSE with high Sr/Y ratios. The Linglong granite shows very uniform Sr–Nd isotopic compositions with initial 87Sr/86Sr ratios of 0.7119–0.7126 and εNd (T) values of −21.3 to −21.6, which are similar to those of the local Neoarchaean basement. The Guojialing suite has variable initial 87Sr/86Sr ratios (0.7108–0.7120) and εNd (T) values (−10.8 to −17.2), which are distinct both from those of the Neoarchaean basement and from those of the local enriched lithospheric mantle inferred from the coeval mafic dykes in the studied area. Detailed petrological and geochemical data indicate that the Linglong suite was derived by partial melting of Neoarchaean metamorphic lower-crustal rocks at depth of > 50 km with a eclogite residue, whereas the Guojialing suite was formed by the reaction of delaminated eclogitic crust-derived melt with the upwelling asthenospheric mantle. The petrogenesis of these two contrasting adakitic granitoids suggests intensive lower-crustal delamination during Early Cretaceous times, following a crustal thickening process from the late stage of the Early Jurassic to early stage of the Late Jurassic with crustal thickness of < 32 km to > 50 km, respectively.
Cancer‐associated fibroblasts (CAFs) are important in tumor microenvironment (TME) driven cancer progression. However, CAFs are heterogeneous and still largely underdefined, better understanding ...their origins will identify new therapeutic strategies for cancer. Here, the authors discovered a new role of macrophage‐myofibroblast transition (MMT) in cancer for de novo generating protumoral CAFs by resolving the transcriptome dynamics of tumor‐associated macrophages (TAM) with single‐cell resolution. MMT cells (MMTs) are observed in non‐small‐cell lung carcinoma (NSCLC) associated with CAF abundance and patient mortality. By fate‐mapping study, RNA velocity, and pseudotime analysis, existence of novel macrophage‐lineage‐derived CAF subset in the TME of Lewis lung carcinoma (LLC) model is confirmed, which is directly transited via MMT from M2‐TAM in vivo and bone‐marrow‐derived macrophages (BMDM) in vitro. Adoptive transfer of BMDM‐derived MMTs markedly promote CAF formation in LLC‐bearing mice. Mechanistically, a Smad3‐centric regulatory network is upregulated in the MMTs of NSCLC, where chromatin immunoprecipitation sequencing(ChIP‐seq) detects a significant enrichment of Smad3 binding on fibroblast differentiation genes in the macrophage‐lineage cells in LLC‐tumor. More importantly, macrophage‐specific deletion and pharmaceutical inhibition of Smad3 effectively block MMT, therefore, suppressing the CAF formation and cancer progression in vivo. Thus, MMT may represent a novel therapeutic target of CAF for cancer immunotherapy.
Here, the authors discovered a direct mechanism of tumor‐associated macrophages for de novo generating protumoral cancer‐associated fibroblasts (CAF) via macrophage‐myofibroblast transition (MMT) by resolving their transcriptome dynamics at single‐cell resolution. Encouragingly, targeting the MMT key regulator Smad3 effectively blocked the production and protumoral actions of CAF, evidencing its translational potential as a novel therapeutic target in the tumour microenvironment for cancer.
Transforming growth factor-β (TGF-β) signaling shows important roles in both physiology and pathology, especially in the progression of inflammatory diseases including cancer. Interestingly, TGF-β ...was first reported as a cancer suppressor, but increasing evidence confirmed its protumoral actions. Paradoxically, TGF-β can be produced by both cancer cells and stromal cells as a signaling network, which actively shapes the tumor microenvironment (TME). Surprisingly, disruption of TGF-β signaling results in both anti-cancer and pro-tumoral phenotypes in experimental cancer models, revealing the unexpected complexity of its downstream pathways for mediating cancer progression. Thus, a better understanding of the underlying mechanisms of TGF-β signaling at the molecular level can bring new insights for developing medications that can precisely separate the anti-cancer actions from the tumor-promoting outcomes. Here, we systematically summarized the latest discoveries of TGF-β signaling in cancer cells and the TME and discussed their translational implications for cancer.
•TGF-β acts as a Tumor suppressor via inducing cell cycle arrest and apoptosis in the initial stages of carcinogenesis.•TGF-β is primary immunomodulator in TME, suppressing anticancer immunity and increasing protumoral elements for cancer growth.•TGF-β enforces immunological homeostasis and tolerance in TME, limiting expansion and function of several immune elements.•The pathogenic downstream of TGF-β signaling networks could be targeted for developing potent and safe immunotherapies.
Background
The increasing prevalence of colorectal cancer (CRC) in China and the paucity of information about relevant expenditure highlight the necessity of better understanding the financial burden ...and effect of CRC diagnosis and treatment. We performed a survey to quantify the direct medical and non‐medical expenditure as well as the resulting financial burden of CRC patients in China.
Methods
We conducted a multicenter, cross‐sectional survey in 37 tertiary hospitals in 13 provinces across China between 2012 and 2014. Each enrolled patient was interviewed using a structured questionnaire. All expenditure data were inflated to the 2014 Chinese Yuan (CNY; 1 CNY = 0.163 USD). We quantified the overall expenditure and financial burden and by subgroup (hospital type, age at diagnosis, sex, education, occupation, insurance type, household income, clinical stage, pathologic type, and therapeutic regimen). We then performed generalized linear modeling to determine the factors associated with overall expenditure.
Results
A total of 2356 patients with a mean age of 57.4 years were included, 57.1% of whom were men; 13.9% of patients had stage I cancer; and the average previous‐year household income was 54,525 CNY. The overall average direct expenditure per patient was estimated to be 67,408 CNY, and the expenditures for stage I, II, III, and IV disease were 56,099 CNY, 59,952 CNY, 67,292 CNY, and 82,729 CNY, respectively. Non‐medical expenditure accounted for 8.3% of the overall expenditure. The 1‐year out‐of‐pocket expenditure of a newly diagnosed patient was 32,649 CNY, which accounted for 59.9% of their previous‐year household income and caused 75.0% of families to suffer an unmanageable financial burden. Univariate analysis showed that financial burden and overall expenditure differed in almost all subgroups (P < 0.05), except for sex. Multivariate analysis showed that patients who were treated in specialized hospitals and those who were diagnosed with adenocarcinoma or diagnosed at a later stage were likely to spend more, whereas those with a lower household income and those who underwent surgery spent less (all P < 0.05).
Conclusions
For patients in China, direct expenditure for the diagnosis and treatment of CRC seemed catastrophic, and non‐medical expenditure was non‐ignorable. The financial burden varied among subgroups, especially among patients with different clinical stages of disease, which suggests that, in China, CRC screening might be cost‐effective.
Angiotensin‐converting enzyme‐2 (ACE2) and Mas receptor are the major components of the ACE2/Ang 1‐7/Mas axis and have been shown to play a protective role in hypertension and hypertensive ...nephropathy individually. However, the effects of dual deficiency of ACE2 and Mas (ACE2/Mas) on Ang II‐induced hypertensive nephropathy remain unexplored, which was investigated in this study in a mouse model of hypertension induced in either ACE2 knockout (KO) or Mas KO mice and in double ACE2/Mas KO mice by subcutaneously chronic infusion of Ang II. Compared with wild‐type (WT) animals, mice lacking either ACE2 or Mas significantly increased blood pressure over 7‐28 days following a chronic Ang II infusion (P < .001), which was further exacerbated in double ACE2/Mas KO mice (P < .001). Furthermore, compared to a single ACE2 or Mas KO mice, mice lacking ACE2/Mas developed more severe renal injury including higher levels of serum creatinine and a further reduction in creatinine clearance, and progressive renal inflammation and fibrosis. Mechanistically, worsen hypertensive nephropathy in double ACE2/Mas KO mice was associated with markedly enhanced AT1‐ERK1/2‐Smad3 and NF‐κB signalling, thereby promoting renal fibrosis and renal inflammation in the hypertensive kidney. In conclusion, ACE2 and Mas play an additive protective role in Ang II‐induced hypertension and hypertensive nephropathy. Thus, restoring the ACE2/Ang1‐7/Mas axis may represent a novel therapy for hypertension and hypertensive nephropathy.
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