Cell Cycle Dysregulation and Renal Fibrosis

Precise regulation of cell cycle is essential for tissue homeostasis and development, while cell cycle dysregulation is associated with many human diseases including renal fibrosis, a common process of various chronic kidney diseases progressing to end-stage renal disease. Under normal physiological conditions, most of the renal cells are post-mitotic quiescent cells arrested in the G0 phase of cell cycle and renal cells turnover is very low. Injuries induced by toxins, hypoxia, and metabolic disorders can stimulate renal cells to enter the cell cycle, which is essential for kidney regeneration and renal function restoration. However, more severe or repeated injuries will lead to maladaptive repair, manifesting as cell cycle arrest or overproliferation of renal cells, both of which are closely related to renal fibrosis. Thus, cell cycle dysregulation of renal cells is a potential therapeutic target for the treatment of renal fibrosis. In this review, we focus on cell cycle regulation of renal cells in healthy and diseased kidney, discussing the role of cell cycle dysregulation of renal cells in renal fibrosis. Better understanding of the function of cell cycle dysregulation in renal fibrosis is essential for the development of therapeutics to halt renal fibrosis progression or promote regression.

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Expression profiles of miRNAs and involvement of miR-100 and miR-34 in regulation of cell cycle arrest in Artemia

Biochemical Journal ◽

10.1042/bj20150116 ◽

2015 ◽

Vol 470 (2) ◽

pp. 223-231 ◽

Cited By ~ 17

Author(s):

Ling-Ling Zhao ◽

Feng Jin ◽

Xiang Ye ◽

Lin Zhu ◽

Jin-Shu Yang ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Cycle Regulation ◽

Cell Cycle Progression ◽

Expression Profiles ◽

Regulatory Mechanisms ◽

Cycle Progression ◽

Cycle Arrest ◽

Regulation Of Cell Cycle ◽

Cycle Regulation

We established an expression profile of miRNA for cell cycle arrest in Artemia and found that miR-100 and miR-34 promote and prevent cell cycle progression respectively. The regulatory mechanisms of these two miRNAs provide insights into cell cycle regulation.

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The Roles of Kidney-Resident ILC2 in Renal Inflammation and Fibrosis

Frontiers in Immunology ◽

10.3389/fimmu.2021.688647 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ryuichi Nagashima ◽

Masayuki Iyoda

Keyword(s):

Kidney Disease ◽

Renal Fibrosis ◽

Kidney Diseases ◽

Lymphoid Cells ◽

Productive Capacity ◽

Kidney Fibrosis ◽

Helminth Infections ◽

Stage Renal Disease ◽

End Stage

Innate lymphoid cells (ILCs) are a recently discovered lymphocyte population with high cytokine productive capacity. Type-2 ILCs (ILC2s) are the most studied, and they exert a rapid type-2 immune response to eliminate helminth infections. Massive and sustainable ILC2 activation induces allergic tissue inflammation, so it is important to maintain correct ILC2 activity for immune homeostasis. The ILC2-activating cytokine IL-33 is released from epithelial cells upon tissue damage, and it is upregulated in various kidney disease mouse models and in kidney disease patients. Various kidney diseases eventually lead to renal fibrosis, which is a common pathway leading to end-stage renal disease and is a chronic kidney disease symptom. The progression of renal fibrosis is affected by the innate immune system, including renal-resident ILC2s; however, the roles of ILC2s in renal fibrosis are not well understood. In this review, we summarize renal ILC2 function and characterization in various kidney diseases and highlight the known and potential contributions of ILC2s to kidney fibrosis.

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A DNA-Damage-Induced Cell Cycle Checkpoint in Arabidopsis

Genetics ◽

10.1093/genetics/164.1.323 ◽

2003 ◽

Vol 164 (1) ◽

pp. 323-334

Author(s):

S B Preuss ◽

A B Britt

Keyword(s):

Cell Cycle ◽

Gamma Radiation ◽

Cell Cycle Progression ◽

Cell Cycle Checkpoint ◽

Phase Cell ◽

Cycle Arrest ◽

Cycle Checkpoint ◽

Radiation Induced ◽

High Doses ◽

Regulation Of Cell Cycle

Abstract Although it is well established that plant seeds treated with high doses of gamma radiation arrest development as seedlings, the cause of this arrest is unknown. The uvh1 mutant of Arabidopsis is defective in a homolog of the human repair endonuclease XPF, and uvh1 mutants are sensitive to both the toxic effects of UV and the cytostatic effects of gamma radiation. Here we find that gamma irradiation of uvh1 plants specifically triggers a G2-phase cell cycle arrest. Mutants, termed suppressor of gamma (sog), that suppress this radiation-induced arrest and proceed through the cell cycle unimpeded were recovered in the uvh1 background; the resulting irradiated plants are genetically unstable. The sog mutations fall into two complementation groups. They are second-site suppressors of the uvh1 mutant's sensitivity to gamma radiation but do not affect the susceptibility of the plant to UV radiation. In addition to rendering the plants resistant to the growth inhibitory effects of gamma radiation, the sog1 mutation affects the proper development of the pollen tetrad, suggesting that SOG1 might also play a role in the regulation of cell cycle progression during meiosis.

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Heme Oxygenase 1: A Defensive Mediator in Kidney Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22042009 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2009

Author(s):

Anne Grunenwald ◽

Lubka T. Roumenina ◽

Marie Frimat

Keyword(s):

Kidney Disease ◽

Heme Oxygenase ◽

Current Knowledge ◽

Kidney Diseases ◽

Heme Oxygenase 1 ◽

Wide Range ◽

Significant Burden ◽

Stage Renal Disease ◽

End Stage ◽

Positive Effect

The incidence of kidney disease is rising, constituting a significant burden on the healthcare system and making identification of new therapeutic targets increasingly urgent. The heme oxygenase (HO) system performs an important function in the regulation of oxidative stress and inflammation and, via these mechanisms, is thought to play a role in the prevention of non-specific injuries following acute renal failure or resulting from chronic kidney disease. The expression of HO-1 is strongly inducible by a wide range of stimuli in the kidney, consequent to the kidney’s filtration role which means HO-1 is exposed to a wide range of endogenous and exogenous molecules, and it has been shown to be protective in a variety of nephropathological animal models. Interestingly, the positive effect of HO-1 occurs in both hemolysis- and rhabdomyolysis-dominated diseases, where the kidney is extensively exposed to heme (a major HO-1 inducer), as well as in non-heme-dependent diseases such as hypertension, diabetic nephropathy or progression to end-stage renal disease. This highlights the complexity of HO-1’s functions, which is also illustrated by the fact that, despite the abundance of preclinical data, no drug targeting HO-1 has so far been translated into clinical use. The objective of this review is to assess current knowledge relating HO-1’s role in the kidney and its potential interest as a nephroprotection agent. The potential therapeutic openings will be presented, in particular through the identification of clinical trials targeting this enzyme or its products.

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Signaling Pathways Involved in Diabetic Renal Fibrosis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.696542 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yuqing Zhang ◽

De Jin ◽

Xiaomin Kang ◽

Rongrong Zhou ◽

Yuting Sun ◽

...

Keyword(s):

Signaling Pathways ◽

Renal Fibrosis ◽

Diabetic Kidney Disease ◽

Interstitial Fibrosis ◽

New Drugs ◽

Therapeutic Effects ◽

Renal Interstitial Fibrosis ◽

Notch Pathways ◽

Stage Renal Disease ◽

End Stage

Diabetic kidney disease (DKD), as the most common complication of diabetes mellitus (DM), is the major cause of end-stage renal disease (ESRD). Renal interstitial fibrosis is a crucial metabolic change in the late stage of DKD, which is always considered to be complex and irreversible. In this review, we discuss the pathological mechanisms of diabetic renal fibrosis and discussed some signaling pathways that are closely related to it, such as the TGF-β, MAPK, Wnt/β-catenin, PI3K/Akt, JAK/STAT, and Notch pathways. The cross-talks among these pathways were then discussed to elucidate the complicated cascade behind the tubulointerstitial fibrosis. Finally, we summarized the new drugs with potential therapeutic effects on renal fibrosis and listed related clinical trials. The purpose of this review is to elucidate the mechanisms and related pathways of renal fibrosis in DKD and to provide novel therapeutic intervention insights for clinical research to delay the progression of renal fibrosis.

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Abstract W P198: Sphingomyelin Synthases Regulate Neuronal Cell Proliferation and Cell Cycle Progression

Stroke ◽

10.1161/str.45.suppl_1.wp198 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Umadevi V Wesley ◽

Daniel Tremmel ◽

Robert Dempsey

Keyword(s):

Cell Cycle ◽

Cell Cycle Regulation ◽

Cell Cycle Progression ◽

Molecular Mechanisms ◽

Neuronal Cell ◽

Artery Occlusion ◽

Cycle Progression ◽

Cycle Arrest ◽

Cycle Regulation ◽

Cerebral Artery Occlusion

Introduction: The molecular mechanisms of cerebral ischemia damage and protection are not completely understood, but a number of reports implicate the contribution of lipid metabolism and cell-cycle regulating proteins in stroke out come. We have previously shown that tricyclodecan-9-yl-xanthogenate (D609) resulted in increased ceramide levels after transient middle cerebral artery occlusion (tMCAO) in spontaneously hypertensive rat (SHR). We hypothesized that D609 induced cell cycle arrest probably by inhibiting sphingomyelin synthase (SMS). In this study, we examined the direct effects of SMS on cell cycle progression and proliferation of neuroblast cells. Methods: Ischemia was induced by middle cerebral artery occlusion (MCAO) and reperfusion. Expression levels were measured by western blot analysis, RT-PCR, and Immunofluorescence staining. SMS1 and 2 expressions were silenced by stable transfection with SMS1/2-targeted shRNA. Cell cycle analysis was performed using Flow cytometry. Data were analyzed using MODFIT cell cycle analysis program. Cell proliferation rate was measured by MTT assay. Results: We have identified that the expression of SMS1is significantly up-regulated in the ischemic hemisphere following MCAO. Neuro-2a cells transfected with SMS specific ShRNA acquired more neuronal like phenotype and exhibited decreased proliferation rate. Also, silencing of both SMS1 and 2 induced cell-cycle arrest as shown by significantly increased percentage of cells in G0/G1 and decreased proportion of cells in S-phase as compared to control cells. This was accompanied by up-regulation of cyclin-dependent kinase (Cdk) inhibitors p21 and decreased levels of phophorylated AKT levels. Furthermore, loss of SMS inhibited the migratory potential of Neuro 2a cells. Summary: Up-regulation of SMS under ischemic/reperfusion conditions suggests that this enzyme potentially contributes to cell cycle regulation and may contribute to maintaining neuronal cell population. Further studies may open up a new direction for identifying the molecular mechanisms of cell cycle regulation and protection following ischemic stroke

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PROTON PUMP INHIBITORS AND THE RISK OF CHRONIC KIDNEY DISEASES: A CRITICAL REVIEW

International Journal of Current Pharmaceutical Research ◽

10.22159/ijcpr.2020v12i5.39783 ◽

2020 ◽

pp. 11-14

Author(s):

SHAREEF J. ◽

SRIDHAR S. B. ◽

SHARIFF A.

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Kidney Disease ◽

Proton Pump Inhibitors ◽

Proton Pump ◽

End Stage Renal Disease ◽

Kidney Diseases ◽

Kidney Injury ◽

Stage Renal Disease ◽

End Stage

Proton pump inhibitors (PPIs) are most widely used medications for acid related gastrointestinal disorders. Accessible evidence based studies suggest that the increased use of PPI is linked to a greater risk of developing kidney diseases. This review aims to determine the association of kidney disease with the use of proton pump inhibitor with various study designs. PubMed, Scopus and Google Scholar databases as well as a reference list of relevant articles were systematically searched for studies by using the following search terms; ‘proton pump inhibitors’, ‘acute kidney injury’, ‘chronic kidney disease’ and ‘end stage renal disease’. Both observational and randomized controlled trials (RCTs) exploring the association of PPI use with kidney disease were eligible for inclusion. A total of 8 articles, including 9 studies (n = 794,349 participants) were identified and included in the review. Majority of the studies showed a higher risk of kidney outcomes in patients taking PPIs, with effect higher of acute kidney injury (4-to 6-fold) compared with chronic kidney disease and end stage renal disease (1.5-to 2.5-fold). However, the studies suggest that the strength of evidence is weak and could not prove causation. The risk increased considerably with the use of high dose of PPIs and prolonged duration of exposure necessitates the monitoring of renal function. Exercising vigilance in PPI use and cessation of proton pump inhibitor when there is no clear indication may be a reasonable approach to reduce the population burden of kidney diseases.

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Long Pentraxin 3 as a Broader Biomarker for Multiple Risk Factors in End-Stage Renal Disease: Association with All-Cause Mortality

Mediators of Inflammation ◽

10.1155/2019/3295725 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Maria João Valente ◽

Susana Rocha ◽

Susana Coimbra ◽

Cristina Catarino ◽

Petronila Rocha-Pereira ◽

...

Keyword(s):

End Stage Renal Disease ◽

Renal Fibrosis ◽

Pentraxin 3 ◽

Dialysis Patients ◽

Inflammatory Biomarker ◽

Multiple Risk Factors ◽

All Cause Mortality ◽

Stage Renal Disease ◽

End Stage ◽

Esrd Patients

Persistent inflammation in end-stage renal disease (ESRD) patients is known to underlie the progression of chronic kidney disease and to be associated with multiple risk factors including malnutrition, atherosclerosis, and cardiovascular disease (CVD). The acute-phase protein pentraxin 3 (PTX3) has a proven potential as a local inflammatory biomarker, but its clinical utility in ESRD remains unclear. Circulating levels of PTX3 and classical inflammatory mediators, including the clinical prototypical C-reactive protein (CRP), were assessed in 246 ESRD patients on dialysis and analysed in relation to the lipid profile, adipokine levels, and nutritional, cardiac, and renal fibrosis markers. Occurrence of deaths was recorded for the following year. Contrarily to the classical inflammatory markers, PTX3 levels were negatively correlated with nutritional markers and associated with a less atherogenic lipid profile. Levels of the cardiac and renal fibrosis markers and of the oxidized LDL/LDL-C ratio were found to be independent determinants of PTX3 concentration. When comparing inflammatory mediators, the increase in the PTX3 levels was the only predictor of all-cause mortality in dialysis patients in a survival model adjusted to all markers under study, other than the inflammatory ones, besides common confounding factors in dialysis. Data support the clinical applicability of PTX3 as a broader inflammatory biomarker than the classical ones, presenting a close association with inflammation, malnutrition, CVD, and renal fibrosis and a great potential to predict all-cause mortality in dialysis patients. The pleiotropic character of PTX3 may be of clinical relevance, and it could be targeted to ameliorate the high morbidity and mortality associated with ESRD.

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An Exosomal Urinary miRNA Signature for Early Diagnosis of Renal Fibrosis in Lupus Nephritis

Cells ◽

10.3390/cells8080773 ◽

2019 ◽

Vol 8 (8) ◽

pp. 773 ◽

Cited By ~ 15

Author(s):

Solé ◽

Moliné ◽

Vidal ◽

Ordi-Ros ◽

Cortés-Hernández

Keyword(s):

Lupus Nephritis ◽

Renal Fibrosis ◽

Target Genes ◽

Early Stage ◽

High Sensitivity ◽

Increased Risk ◽

Chronicity Index ◽

Stage Renal Disease ◽

End Stage

For lupus nephritis (LN) management, it is very important to detect fibrosis at an early stage. Urinary exosomal miRNAs profiling can be used as a potential multi-marker phenotyping tool to identify early fibrosis. We isolated and characterised urinary exosomes and cellular pellets from patients with biopsy-proven LN (n = 45) and healthy controls (n = 20). LN chronicity index (CI) correlated with urinary exosomal miR-21, miR-150, and miR-29c (r = 0.565, 0.840, −0.559, respectively). This miRNA profile distinguished low CI from moderate-high CI in LN patients with a high sensitivity and specificity (94.4% and 99.8%). Furthermore, this multimarker panel predicted an increased risk of progression to end-stage renal disease (ESRD). Pathway analysis identified VEGFA and SP1 as common target genes for the three miRNAs. Immunohistochemistry in LN renal biopsies revealed a significant increase of COL1A1 and COL4A1 correlated with renal chronicity. SP1 decreased significantly in the high-CI group (p = 0.002). VEGFA levels showed no differences. In vitro experiments suggest that these miRNA combinations promote renal fibrosis by increasing profibrotic molecules through SP1 and Smad3/TGFβ pathways. In conclusion, a urinary exosomal multimarker panel composed of miR-21, miR-150, and miR-29c provides a non-invasive method to detect early renal fibrosis and predict disease progression in LN.

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