scholarly journals Permissive effect of GSK3β on profibrogenic plasticity of renal tubular cells in progressive chronic kidney disease

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Bohan Chen ◽  
Pei Wang ◽  
Xianhui Liang ◽  
Chunming Jiang ◽  
Yan Ge ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Binding Protein ◽  
Renal Tubules ◽  
Genetic Ablation ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Renal Fibrogenesis ◽  
Tgf Β1

AbstractRenal tubular epithelial cells (TECs) play a key role in renal fibrogenesis. After persistent injuries that are beyond self-healing capacity, TECs will dedifferentiate, undergo growth arrest, convert to profibrogenic phenotypes, and resort to maladaptive plasticity that ultimately results in renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3β is centrally implicated in kidney injury. However, its role in renal fibrogenesis is obscure. Analysis of publicly available kidney transcriptome database demonstrated that patients with progressive chronic kidney disease (CKD) exhibited GSK3β overexpression in renal tubulointerstitium, in which the predefined hallmark gene sets implicated in fibrogenesis were remarkably enriched. In vitro, TGF-β1 treatment augmented GSK3β expression in TECs, concomitant with dedifferentiation, cell cycle arrest at G2/M phase, excessive accumulation of extracellular matrix, and overproduction of profibrotic cytokines like PAI-1 and CTGF. All these profibrogenic phenotypes were largely abrogated by GSK3β inhibitors or by ectopic expression of a dominant-negative mutant of GSK3β but reinforced in cells expressing the constitutively active mutant of GSK3β. Mechanistically, GSK3β suppressed, whereas inhibiting GSK3β facilitated, the activity of cAMP response element-binding protein (CREB), which competes for CREB-binding protein, a transcriptional coactivator essential for TGF-β1/Smad signaling pathway to drive TECs profibrogenic plasticity. In vivo, in mice with folic acid-induced progressive CKD, targeting of GSK3β in renal tubules via genetic ablation or by microdose lithium mitigated the profibrogenic plasticity of TEC, concomitant with attenuated interstitial fibrosis and tubular atrophy. Collectively, GSK3β is likely a pragmatic therapeutic target for averting profibrogenic plasticity of TECs and improving renal fibrosis.

scholarly journals Mesenchymal Stem Cell-Derived Exosome miR-21-3p Prevents Renal Fibrosis

2020 ◽  
Author(s):  
Zongying Li ◽  
Shuyi Cao
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Paracrine Effects ◽  
Downstream Target ◽  
Renal Tubular Epithelium ◽  
Pathological Result ◽  
Renal Tubular ◽  
Preclinical And Clinical Studies ◽  
Tgf Β1

Abstract Background: Renal fibrosis is the pathological result of excessive deposition of extracellular matrix (ECM) in the process of chronic kidney disease, but its mechanism is not clear. Preclinical and clinical studies have shown that mesenchymal stem cells (MSCs) can delay the progression of chronic kidney disease (CKD).MSCs exerts its therapeutic effect mainly through paracrine effects, such as exosome, to change the cellular microenvironment. Here, we would explore the function of MSCs derived exosome in renal fibrosis.Materials and Methods: MRNA, microRNAs and proteins carried by exosomes produced by MSCs could save damaged cells by regulating endogenous molecules to regulate apoptosis, inflammation, fibrosis and angiogenesis. Results: In this study, we observed that exogenous miR-21-3p, interacted with smad2, the downstream target of miR-21-3p, which prevented renal fibrosis in UUO mice, and alleviate fibrosis in TGF-β1-induced renal tubular epithelium cells (HK-2). Then we forced expression of miR-21-3p in MSCs and isolated the exosomes. The extractive exosome-miR-21-3p treatment blocked renal fibrosis in UUO mice and alleviated fibrosis in TGF-β1-induced HK-2 cells. Conclusion: Taken together, Overexpression of miR-21-3p prevented CKD-induced renal fibrosis via exosome-mediated miR-21-3p transfer. These results suggest possible therapeutic strategies for using exosome delivery of miR-21-3p to treat complications of CKD.

Reduced urinary corin levels in patients with chronic kidney disease

2013 ◽  
Vol 124 (12) ◽  
pp. 709-717 ◽  
Author(s):  
Chaodong Fang ◽  
Lei Shen ◽  
Liang Dong ◽  
Meng Liu ◽  
Sensen Shi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Human Urine ◽  
Animal Studies ◽  
Kidney Tissue ◽  
Renal Tubules ◽  
Tissue Samples ◽  
Protein Levels ◽  
Normal Individuals ◽  
Renal Tubular

Corin is a cardiac protease that regulates BP (blood pressure) by activating natriuretic peptides. Recent animal studies identified corin expression in the kidney where it may regulate renal function. In the present study, we tested the hypothesis that corin may be present in human urine and that urinary corin levels may be altered in patients with kidney disease. We obtained urine and kidney tissue samples from normal individuals and CKD (chronic kidney disease) patients. Using ELISA, we detected corin protein in human urine. In normal individuals, urinary corin levels did not correlate with that of plasma, indicating that urinary corin is probably of kidney origin. Compared with normal controls, CKD patients had markedly reduced urinary corin levels and this reduction correlated with disease severity. By immunostaining, human corin protein was identified on the epithelial cell surface in renal tubules. The renal corin mRNA and protein levels were significantly lower in CKD patients than non-CKD controls. The results indicate that renal tubular corin may be shed into urine and that urinary and renal corin levels were reduced in CKD patients. These data suggest that reduced corin levels in the kidney may reflect the underlying pathology in CKD.

scholarly journals Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage–myofibroblast transition

2020 ◽  
Vol 117 (34) ◽  
pp. 20741-20752 ◽  
Author(s):  
Patrick Ming-Kuen Tang ◽  
Ying-ying Zhang ◽  
Jun Xiao ◽  
Philip Chiu-Tsun Tang ◽  
Jeff Yat-Fai Chung ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Early Stage ◽  
Transcriptional Level ◽  
Pou Domain ◽  
Renal Fibrogenesis ◽  
Tgf Β1

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.

scholarly journals P0547THE DELETION OF AKT1 ATTENUATES RENAL FIBROSIS AND TUBULAR EPITHELIAL-MESENCHYMAL TRANSITION DURING ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE PROGRESSION

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Byung Min Ye ◽  
Il Young Kim ◽  
Min Jeong Kim ◽  
Soo Bong Lee ◽  
Dong Won Lee ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Kidney Injury ◽  
Wild Type ◽  
Ckd Progression ◽  
Mesenchymal Transition ◽  
Tgf Β1

Abstract Background and Aims Acute kidney injury (AKI) is an underestimated, yet important risk factor for the development of chronic kidney disease (CKD), which is characterized by the tubulointerstitial fibrosis and tubular epithelial-mesenchymal transition (EMT). Akt has been reported to be involved in renal fibrosis and EMT. Thus, we investigated the role of Akt1, one of the three Akt isoforms, in the murine model of AKI to CKD progression. Method We subjected the wild type and Akt1−/− mice to unilateral ischemia-reperfusion injury (UIRI). UIRI was induced by clamping the left renal artery for 30 min followed by reperfusion. After 6 weeks of UIRI, the renal fibrosis and EMT were assessed by histology, immunohistochemistry, and western blot. Results After 6 weeks after UIRI, we found that Akt1, not Akt2 or Akt3, was activated in UIRI-kidney. The tubulointerstitial fibrosis was significantly alleviated in Akt1−/− mice compared with the wild type (WT) mice. Besides, the deletion of Akt1 decreased the expression of the vimentin and α-SMA and increased the expression of E-cadherin, indicating the suppression of tubular EMT. However, there was no difference in the activity of TGF-β1/Smad signalling, which is the potent inducer of renal fibrosis and EMT, between WT mice and Akt1−/− mice. The deletion of Akt1 also increased the GSK-3β activity and decreased the expression of β-catenin, Snail, and twist1. Conclusion Our findings demonstrate that the deletion of Akt1 attenuates the renal fibrosis and tubular EMT independently of TGF-β1/Smad signalling during the AKI to CKD progression. Akt1 may be the therapeutic target against the AKI to CKD progression.

The miR-200 family regulates TGF-β1-induced renal tubular epithelial to mesenchymal transition through Smad pathway by targeting ZEB1 and ZEB2 expression

2012 ◽  
Vol 302 (3) ◽  
pp. F369-F379 ◽  
Author(s):  
Mingxia Xiong ◽  
Lei Jiang ◽  
Yang Zhou ◽  
Wenjing Qiu ◽  
Li Fang ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Expression Profiles ◽  
Renal Tubules ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Renal Tubular ◽  
Novel Therapeutic Strategies ◽  
Tgf Β1

Most chronic kidney injuries inevitably progress to irreversible renal fibrosis. Tubular epithelial-to-mesenchymal transition (EMT) is recognized to play pivotal roles in the process of renal fibrosis. However, a comprehensive understanding of the pathogenesis of renal scar formation and progression remains an urgent task for renal researchers. The endogenously produced microRNAs (miRNAs), proved to play important roles in gene regulation, probably regulate most genes involved in EMT. In this study, we applied microarray analysis to investigate the expression profiles of miRNA in murine interstitial fibrotic kidneys induced by unilateral ureteral obstruction (UUO). It was found that miR-200a and miR-141, two members of the miR-200 family, were downregulated at the early phase of UUO. In TGF-β1-induced tubular EMT in vitro, it was also found that the members of the miR-200 family were downregulated in a Smad signaling-dependent manner. It was demonstrated that the miR-200 family was responsible for protecting tubular epithelial cells from mesenchymal transition by target suppression of zinc finger E-box-binding homeobox (ZEB) 1 and ZEB2, which are E-cadherin transcriptional repressors. The results suggest that downregulation of the miR-200 family initiates the dedifferentiation of renal tubules and progression of renal fibrosis, which might provide important targets for novel therapeutic strategies.

scholarly journals Uncovering Bupi Yishen Formula Pharmacological Mechanisms Against Chronic Kidney Disease by Network Pharmacology and Experimental Validation

2021 ◽  
Vol 12 ◽  
Author(s):  
Difei Zhang ◽  
Bingran Liu ◽  
Xina Jie ◽  
Jiankun Deng ◽  
Zhaoyu Lu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Inflammatory Responses ◽  
Experimental Studies ◽  
Public Health Problem ◽  
Network Pharmacology ◽  
High Morbidity ◽  
Pharmacological Mechanism ◽  
Tgf Β1

Chronic kidney disease (CKD) is a leading public health problem with high morbidity and mortality, but the therapies remain limited. Bupi Yishen Formula (BYF) - a patent traditional Chinese medicine (TCM) formula - has been proved to be effective for CKD treatment in a high-quality clinical trial. However, BYF’s underlying mechanism is unclear. Thus, we aimed to reveal BYF pharmacological mechanism against CKD by network pharmacology and experimental studies. Network pharmacology-based analysis of the drug-compound-target interaction was used to predict the potential pharmacological mechanism and biological basis of BYF. We performed a comprehensive study by detecting the expression levels of fibrotic and inflammatory markers and main molecules of candidate signal pathway in adenine-induced CKD rats and TGF-β1-induced HK-2 cells with the treatment of BYF by western blotting and RT-qPCR analyses. Using small interfering RNA, we assessed the effect of BYF on the TLR4-mediated NF-κB mechanism for CKD renal fibrosis and inflammation. Network pharmacology analysis results identified 369 common targets from BYF and CKD. Based on these common targets, the BYF intervention pathway was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. We found that Toll-like receptor (TLR) and NF-κB signaling pathways were enriched. Then, we demonstrated that BYF significantly improved the adenine-induced CKD rat model condition by kidney dysfunction improvement and reversing renal fibrosis and inflammation. Subsequently, we investigated BYF’s effect on the TLR4/NF-κB signaling pathway. We found that TLR4 and phospho-NF-κB (p-p65 and p-IKβα) expression was significantly upregulated in adenine-induced CKD rats, then partially downregulated by BYF. Furthermore, BYF inhibited fibrotic and inflammatory responses, as well as TLR4, p-p65, and p-IKβα in TGF-β1-induced HK-2 cells. Additionally, the BYF inhibitory effect on fibrosis and inflammation, and NF-κB pathway activation were significantly reduced in TGF-β1-induced HK-2 cells transfected with TLR4 siRNA. Altogether, these findings demonstrated that the suppression of TLR4-mediated NF-κB signaling was an important anti-fibrotic and anti-inflammatory mechanism for BYF against CKD. It also provided a molecular basis for new CKD treatment drug candidates.

Abstract 18092: Source of Galectin-3 in Human Heart Failure, Chronic Kidney Disease and Cardio-renal Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Imad Hussain ◽  
Mariam P Alexander ◽  
Joseph J Maleszewski ◽  
Naveen L Pereira ◽  
Margaret M Redfield
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Renal Failure ◽  
Kidney Disease ◽  
Human Heart ◽  
Cardiac Transplant ◽  
Renal Tubular Cells ◽  
Galectin 3 ◽  
Cd 68 ◽  
Renal Tubular

Background: Galectin-3 (Gal-3) may promote cardiac and renal fibrosis in heart failure (HF). Plasma Gal-3 levels predict outcome in HF but are tightly correlated with renal function. The source of Gal-3 in human HF, chronic kidney disease (CKD) or cardio-renal failure (HF+CKD) is unclear. Objective: To assess Gal-3 presence and location in human heart or kidney tissue from patients with HF, CKD or HF+CKD. Methods: Plasma Gal-3 levels and LV tissue explanted at time of cardiac transplant in systolic HF (n=15) and autopsy renal sections from patients with normal kidneys (n=4), CKD (n=17) or CKD+HF (n=14) were examined (H&E, Masson’s trichrome and CD-68 and Gal-3 immunohistochemistry). In the systolic HF patients, we quantified the number of Gal-3+/CD-68+ cells per HPF in LV tissue and assessed the correlation with plasma Gal-3 levels. In autopsy renal tissue, we derived a Composite Gal-3 Score (CG3S) incorporating the % of Gal-3+ tubules per HPF, % of Gal-3+ cells/tubule per HPF, and intensity of Gal-3 staining and assessed the correlation of the CG3S with ante-mortem estimated glomerular filtration rate(eGFR). Renal macrophage Gal-3 staining was also assessed. Results: In systolic HF LV tissue, Gal-3 was present in macrophages rather than myocytes but Gal-3+/CD-68+ cells per HPF was not correlated with plasma Gal-3 levels (p> 0.9) which correlated inversely with eGFR (r = -0.89 for log Gal-3 vs eGFR, p<0.0001). In the kidney, Gal-3 was not present in macrophages but was localized to renal tubular cells (Figure). The CG3S increased exponentially as eGFR decreased (r = - 0.88 for log CG3S versus eGFR; p<0.0001) and this relationship was not different (p=0.44) in patients with or without HF (Figure). The log CG3S correlated with the degree of fibrosis (tubulointerstitial scarring) in the kidney (r=0.88; p<0.0001). Conclusion: Collectively, these data suggest that plasma Gal-3 is predominantly of renal tubular epithelial origin in human HF, CKD, and CKD+HF.

scholarly journals Chronic effects of repeated low-dose cisplatin treatment in mouse kidneys and renal tubular cells

2019 ◽  
Vol 317 (6) ◽  
pp. F1582-F1592 ◽  
Author(s):  
Ying Fu ◽  
Juan Cai ◽  
Fanghua Li ◽  
Zhiwen Liu ◽  
Shaoqun Shu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Low Dose ◽  
Interstitial Fibrosis ◽  
Cell Model ◽  
Repeated Treatment ◽  
Renal Tubular Cells ◽  
Acute Kidney Disease ◽  
Atubular Glomeruli ◽  
Renal Tubular

Cisplatin is a commonly used chemotherapeutic drug for cancer treatment, but its nephrotoxicity may lead to the deterioration of renal function. Previous work has been focused on cisplatin-induced acute kidney disease, whereas the mechanism of chronic kidney disease after cisplatin chemotherapy is largely unknown. In the present study, we have characterized the mouse model of chronic kidney defects induced by repeated low-dose cisplatin treatment. We have also established a relevant cell culture model. In the animal model, C57 mice were given weekly injection of 8 mg/kg cisplatin for 4 wk. This led to a sustained decline of kidney function. These mice showed loss of kidney mass, interstitial fibrosis, continued activation of inflammatory cytokines, and appearance of atubular glomeruli. In the cell model, the BUMPT mouse proximal tubular cell line was treated four times with 1–2 μM cisplatin, resulting in low levels of apoptosis and the expression of fibrosis proteins and profibrotic factors. These data suggest that repeated treatment with low-dose cisplatin causes long-term renal pathologies with characteristics of chronic kidney disease.

scholarly journals Artemether ameliorates kidney injury by restoring redox imbalance and improving mitochondrial function in Adriamycin nephropathy in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Pengxun Han ◽  
Yuchun Cai ◽  
Yao Wang ◽  
Wenci Weng ◽  
Yinghui Chen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Function ◽  
Biological Effects ◽  
Kidney Injury ◽  
High Energy ◽  
Redox Imbalance ◽  
Renal Tubular Cells ◽  
Adriamycin Nephropathy ◽  
Renal Tubular ◽  
Tgf Β1

AbstractThe kidney is a high-energy demand organ rich in mitochondria especially renal tubular cells. Emerging evidence suggests that mitochondrial dysfunction, redox imbalance and kidney injury are interconnected. Artemether has biological effects by targeting mitochondria and exhibits potential therapeutic value for kidney disease. However, the underlying molecular mechanisms have not been fully elucidated. This study was performed to determine the effects of artemether on Adriamycin-induced nephropathy and the potential mechanisms were also investigated. In vivo, an Adriamycin nephropathy mouse model was established, and mice were treated with or without artemether for 2 weeks. In vitro, NRK-52E cells were stimulated with TGF-β1 and treated with or without artemether for 24 h. Then renal damage and cell changes were evaluated. The results demonstrated that artemether reduced urinary protein excretion, recovered podocyte alterations, attenuated pathological changes and alleviated renal tubular injury. Artemether also downregulated TGF-β1 mRNA expression levels, inhibited tubular proliferation, restored tubular cell phenotypes and suppressed proliferation-related signalling pathways. In addition, artemether restored renal redox imbalance, increased mtDNA copy number and improved mitochondrial function. In summary, we provided initial evidence that artemether ameliorates kidney injury by restoring redox imbalance and improving mitochondrial function in Adriamycin nephropathy in mice. Artemether may be a promising agent for the treatment kidney disease.

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