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Renal Failure Dec 2023Type XXVIII collagen (COL28) is involved in cancer and lung fibrosis. COL28 polymorphisms and mutations might be involved in kidney fibrosis, but the exact role of COL28...
Type XXVIII collagen (COL28) is involved in cancer and lung fibrosis. COL28 polymorphisms and mutations might be involved in kidney fibrosis, but the exact role of COL28 in renal fibrosis is unknown. This study explored the function of COL28 in renal tubular cells by examining the expression of COL28 mRNA and the effects of COL28 overexpression in human tubular cells. COL28 mRNA expression and localization were observed in normal and fibrotic kidney tissues from humans and mice using real-time PCR, western blot, immunofluorescence, and immunohistochemistry. The consequences of COL28 overexpression on cell proliferation, migration, cell polarity, and epithelial-to-mesenchymal transition (EMT) induced by TGF-β1 were examined in human tubular HK-2 cells. COL28 expression was low in human normal renal tissues, mainly observed in the renal tubular epithelial cells and especially in proximal renal tubules. COL28 protein expression in human and mouse obstructive kidney disease was higher than in normal tissues ( < 0.05) and more significant in the UUO2-Week than the UUO1-Week group. The overexpression of COL28 promoted HK-2 cell proliferation and enhanced their migration ability (all < 0.05). TGF-β1 (10 ng/ml) induced COL28 mRNA expression in HK-2 cells, decreased E-cadherin and increased α-SMA in the COL28-overexpression group compared with controls ( < 0.05). ZO-1 expression decreased while COL6 increased in the COL28-overexpression group compared with controls ( < 0.05). In conclusion, COL28 overexpression promotes the migration and proliferation of renal tubular epithelial cells. The EMT could also be involved. COL28 could be a therapeutic target against renal- fibrotic diseases.
Topics: Animals; Humans; Mice; Cell Proliferation; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibrosis; Kidney Diseases; Kidney Tubules; RNA, Messenger; Transforming Growth Factor beta1
PubMed: 36883360
DOI: 10.1080/0886022X.2023.2187236 -
Renal Failure Dec 2022Hydrogen sulfide (HS), an endogenous gaseous signaling transmitter, has gained recognition for its physiological effects. In this review, we aim to summarize and discuss... (Review)
Review
Hydrogen sulfide (HS), an endogenous gaseous signaling transmitter, has gained recognition for its physiological effects. In this review, we aim to summarize and discuss existing studies about the roles of HS in renal functions and renal disease as well as the underlying mechanisms. HS is mainly produced by four pathways, and the kidneys are major HS-producing organs. Previous studies have shown that HS can impact multiple signaling pathways via sulfhydration. In renal physiology, HS promotes kidney excretion, regulates renin release and increases ATP production as a sensor for oxygen. HS is also involved in the development of kidney disease. HS has been implicated in renal ischemia/reperfusion and cisplatin-and sepsis-induced kidney disease. In chronic kidney diseases, especially diabetic nephropathy, hypertensive nephropathy and obstructive kidney disease, HS attenuates disease progression by regulating oxidative stress, inflammation and the renin-angiotensin-aldosterone system. Despite accumulating evidence from experimental studies suggesting the potential roles of HS donors in the treatment of kidney disease, these results need further clinical translation. Therefore, expanding the understanding of HS can not only promote our further understanding of renal physiology but also lay a foundation for transforming HS into a target for specific kidney diseases.
Topics: Diabetic Nephropathies; Humans; Hydrogen Sulfide; Kidney; Oxidative Stress; Renal Insufficiency, Chronic
PubMed: 35930288
DOI: 10.1080/0886022X.2022.2107936 -
Molecular Medicine Reports Sep 2018The aim of the present study was to explore the candidate genes, chemicals and mechanisms of congenital obstructive nephropathy (CON). The gene expression profiles of...
The aim of the present study was to explore the candidate genes, chemicals and mechanisms of congenital obstructive nephropathy (CON). The gene expression profiles of GSE48041, including 24 kidney tissue samples from megabladder (mgb‑/‑) mouse were downloaded from the Gene Expression Omnibus database. Samples were divided into 4 groups: Control, mild, moderate and severe. Differentially expressed genes (DEGs), protein‑protein interaction network, Kyoto Encyclopedia of Genes and Genomes pathways and transcription factor (TF)‑target gene analyses were performed on Set 1 (mild, moderate and severe groups), while Gene Ontology (GO) function enrichment analysis and chemical investigation were performed on Set 2 (severe group). A total of 187 and 139 DEGs were obtained in Set 1 and Set 2, respectively. Chemical carcinogenesis [enriched by genes such as Carbonyl reductase 1 (CBR1)] was one of the most prominent pathways in Set 1. GO analysis for Set 2 revealed that DEGs were mainly assembled in functions such as cellular response to interleukin‑1 and cellular response to tumor necrosis. Furthermore, genes such as Fos Proto‑Oncogene (FOS) were co‑regulated by TFs including RNA polymerase II subunit A (Polr2a) and serum response factor (Srf). Chemical cyclosporine served the most important role in Set 2 by targeting several DEGs in Set 2. DEGs such as CBR1 and FOS, TFs including Polr2a and Srf, and pathways such as chemical carcinogenesis may serve important roles in the process of CON. Interleukin‑1 and tumor necrosis function may be novel targets for CON gene therapy. Furthermore, cyclosporine may be a promising option for future CON therapy.
Topics: Animals; Carbonyl Reductase (NADPH); Computational Biology; Databases, Genetic; Gene Expression Regulation; Gene Regulatory Networks; Humans; Kidney; Kidney Diseases; Mice; Mice, Knockout; Protein Interaction Maps; Transcription Factors; Transcriptome
PubMed: 30015886
DOI: 10.3892/mmr.2018.9284 -
Kidney International Jan 2013Occlusion of the renal arteries can threaten the viability of the kidney when severe, in addition to accelerating hypertension and circulatory congestion. Renal artery... (Review)
Review
Occlusion of the renal arteries can threaten the viability of the kidney when severe, in addition to accelerating hypertension and circulatory congestion. Renal artery stenting procedures have evolved from a treatment mainly for renovascular hypertension to a maneuver capable of recovering threatened renal function in patients with 'ischemic nephropathy' and improving management of congestive heart failure. Improved catheter design and techniques have reduced, but not eliminated, hazards associated with renovascular stenting. Expanded use of endovascular stent grafts to treat abdominal aortic aneurysms has introduced a new indication for renal artery stenting to protect the renal circulation when grafts cross the origins of the renal arteries. Although controversial, prospective randomized trials to evaluate the added benefit of revascularization to current medical therapy for atherosclerotic renal artery stenosis until now have failed to identify major benefits regarding either renal function or blood pressure control. These studies have been limited by selection bias and have been harshly criticized. While studies of tissue oxygenation using blood-oxygen-level-dependent (BOLD) magnetic resonance establish that kidneys can adapt to reduced blood flow to some degree, more severe occlusive disease leads to cortical hypoxia associated with microvascular rarefaction inflammatory injury, and fibrosis. Current research is directed toward identifying pathways of irreversible kidney injury due to vascular occlusion and to increase the potential for renal repair after restoring renal artery patency. The role of nephrologists likely will focus upon recognizing the limits of renal adaptation to vascular disease and identifying kidneys truly at risk for ischemic injury at a time point when renal revascularization can still be of benefit to recovering kidney function.
Topics: Atherosclerosis; Catheters; Humans; Hypertension, Renovascular; Ischemia; Kidney Diseases; Renal Artery; Renal Artery Obstruction; Stents; Vascular Surgical Procedures
PubMed: 23151953
DOI: 10.1038/ki.2012.363 -
Pharmaceutical Biology Dec 2023Salvianolic acid B (SAB) can alleviate renal fibrosis and improve the renal function.
CONTEXT
Salvianolic acid B (SAB) can alleviate renal fibrosis and improve the renal function.
OBJECTIVE
To investigate the effect of SAB on renal tubulointerstitial fibrosis and explore its underlying mechanisms.
MATERIALS AND METHODS
Male C57 mice were subjected to unilateral ureteric obstruction (UUO) and aristolochic acid nephropathy (AAN) for renal fibrosis indication. Vehicle or SAB (10 mg/kg/d, i.p.) were given consecutively for 2 weeks in UUO mice while 4 weeks in AAN mice. The serum creatinine (Scr) and blood urine nitrogen (BUN) were measured. Masson's trichrome staining and the fibrotic markers (FN and α-SMA) were used to evaluate renal fibrosis. NRK-49F cells exposed to 2.5 ng/mL TGF-β were treated with SAB in the presence or absence of 20 μM 3-DZNep, an inhibitor of EZH2. The protein expression of EZH2, H3k27me3 and PTEN/Akt signaling pathway in renal tissue and NRK-49F cells were measured by Western blots.
RESULTS
SAB significantly improved the levels of Scr by 24.3% and BUN by 35.7% in AAN mice. SAB reduced renal interstitial collagen deposition by 34.7% in UUO mice and 72.8% in AAN mice. Both and studies demonstrated that SAB suppressed the expression of FN and α-SMA, increased PTEN and decreased the phosphorylation of Akt, which were correlated with the down-regulation of EZH2 and H3k27me3. The inhibition of EZH2 attenuated the anti-fibrotic effects of SAB in NRK-49Fs.
CONCLUSION
SAB might have therapeutic potential on renal fibrosis of CKD through inhibiting EZH2, which encourages further clinical trials.
Topics: Animals; Male; Mice; Fibrosis; Histones; Kidney; Kidney Diseases; Proto-Oncogene Proteins c-akt; Transforming Growth Factor beta1; Ureteral Obstruction; Benzofurans; Depsides; Enhancer of Zeste Homolog 2 Protein; PTEN Phosphohydrolase
PubMed: 36524761
DOI: 10.1080/13880209.2022.2148169 -
Journal of the American Society of... Apr 2020Hereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA...
BACKGROUND
Hereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown.
METHODS
Using animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies.
RESULTS
Adenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term . In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of , , or had no effect on the manifestations of 2,8-DHA nephropathy.
CONCLUSIONS
Rodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.
Topics: Adenine; Adenine Phosphoribosyltransferase; Adult; Animals; Cohort Studies; Diet; Disease Models, Animal; Female; Humans; Infant; Kidney Diseases; Male; Metabolism, Inborn Errors; Mice; Middle Aged; Urolithiasis
PubMed: 32086278
DOI: 10.1681/ASN.2019080827 -
Clinical Journal of the American... Oct 2012Obstructive nephropathy is a leading cause of CKD in children. The assessment of severity of renal impairment and the prediction of which children will progress to renal...
BACKGROUND AND OBJECTIVES
Obstructive nephropathy is a leading cause of CKD in children. The assessment of severity of renal impairment and the prediction of which children will progress to renal failure are, however, challenging.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
This case-control study measured the urinary excretion of candidate biomarkers in 27 prevalent case-patients with posterior urethral valves (PUVs) and 20 age-matched controls, correlated their urinary concentration with GFR, and analyzed receiver-operating characteristic (ROC) curve and regression analyses to assess their performance as tests for low GFR.
RESULTS
The median urinary protein-to-creatinine ratio was higher in children with PUV (45 g/mol; range, 5-361 g/mol) than in controls (7 g/mol; range, 3-43 g/mol) (P<0.01) and correlated inversely with renal function (r = -0.44; P<0.05). In whole urine, excretion of aquaporin-2 was significantly decreased, whereas that of TGFβ and L1 cell adhesion molecule (L1CAM) was significantly increased. Whole-urine TGFβ excretion correlated inversely with GFR (r = -0.53; P<0.05). As tests for low GFR, whole-urine TGFβ, L1CAM, and urinary protein-to-creatinine ratio performed best, with areas under the ROC curves of 0.788, 0.795, and 0.814, respectively. By linear regression analysis, whole-urine TGFβ, L1CAM, and urinary protein-to-creatinine ratio were associated with low GFR in the case-patients.
CONCLUSIONS
Candidate biomarkers of obstructive nephropathy can be readily measured in whole urine and in urine exosomes. In boys with PUV, these biomarkers correlate with GFR.
Topics: Adolescent; Antigens, CD; Aquaporin 2; Area Under Curve; Biomarkers; Cadherins; Case-Control Studies; Child; Child, Preschool; Creatinine; Disease Progression; Exosomes; Feasibility Studies; Glomerular Filtration Rate; Humans; Infant; Kidney; Kidney Diseases; Kidney Failure, Chronic; Linear Models; Logistic Models; Male; Neural Cell Adhesion Molecule L1; Predictive Value of Tests; Proteinuria; Proteomics; ROC Curve; TRPV Cation Channels; Transforming Growth Factor beta; Urethral Obstruction; Urinalysis; Vacuolar Proton-Translocating ATPases; beta Catenin
PubMed: 22859744
DOI: 10.2215/CJN.09640911 -
Scientific Reports Feb 2020TRPM7 belongs to the Transient Receptor Potential Melastatin family of ion channels and is a divalent cation-conducting ion channel fused with a functional kinase. TRPM7...
TRPM7 belongs to the Transient Receptor Potential Melastatin family of ion channels and is a divalent cation-conducting ion channel fused with a functional kinase. TRPM7 plays a key role in a variety of diseases, including neuronal death in ischemia, cancer, cardiac atrial fibrillation, malaria invasion. TRPM7 is aberrantly over-expressed in lung, liver and heart fibrosis. It is also overexpressed after renal ischemia-reperfusion, an event that induces kidney injury and fibrosis. However, the role of TRPM7 in kidney fibrosis is unclear. Using the unilateral ureteral obstruction (UUO) mouse model, we examined whether TRPM7 contributes to progressive renal damage and fibrosis. We find that TRPM7 expression increases in UUO kidneys. Systemic application of NS8593, a known TRPM7 inhibitor, prevents kidney atrophy in UUO kidneys, retains tubular formation, and reduces TRPM7 expression to normal levels. Cell proliferation of both tubular epithelial cells and interstitial cells is reduced by NS8593 treatment in UUO kidneys, as are TGF-β1/Smad signaling events. We conclude that TRPM7 is upregulated during inflammatory renal damage and propose that pharmacological intervention targeting TRPM7 may prove protective in progressive kidney fibrosis.
Topics: 1-Naphthylamine; Animals; Disease Models, Animal; Fibrosis; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Signal Transduction; TRPM Cation Channels; Transforming Growth Factor beta1; Ureteral Obstruction
PubMed: 32047249
DOI: 10.1038/s41598-020-59355-y -
Kidney International Feb 2015Tumor necrosis factor (TNF), initially reported to induce tumor cell apoptosis and cachexia, is now considered a central mediator of a broad range of biological... (Review)
Review
Tumor necrosis factor (TNF), initially reported to induce tumor cell apoptosis and cachexia, is now considered a central mediator of a broad range of biological activities from cell proliferation, cell death and differentiation to induction of inflammation and immune modulation. TNF exerts its biological responses via interaction with two cell surface receptors: TNFR1 and TNFR2. (TNFRs). These receptors trigger shared and distinct signaling pathways upon TNF binding, which in turn result in cellular outputs that may promote tissue injury on one hand but may also induce protective, beneficial responses. Yet the role of TNF and its receptors specifically in renal disease is still not well understood. This review describes the expression of the TNFRs, the signaling pathways induced by them and the biological responses of TNF and its receptors in various animal models of renal diseases, and discusses the current outcomes from use of TNF biologics and TNF biomarkers in renal disorders.
Topics: Acute Kidney Injury; Animals; Carcinoma, Renal Cell; Diabetic Nephropathies; Graft Rejection; Humans; Kidney Diseases; Kidney Neoplasms; Kidney Transplantation; Models, Biological; Nephritis; Receptors, Tumor Necrosis Factor; Signal Transduction; Tumor Necrosis Factor-alpha; Ureteral Obstruction
PubMed: 25140911
DOI: 10.1038/ki.2014.285 -
American Journal of Nephrology 2012The major evolutionary advance represented in the human immune system is a mechanism of antigen-directed immunity in which tumor necrosis factor (TNF)-α and TNF... (Review)
Review
The major evolutionary advance represented in the human immune system is a mechanism of antigen-directed immunity in which tumor necrosis factor (TNF)-α and TNF receptors (TNFRs) play essential roles. Binding of TNF-α to the 55-kDa type I TNFR (TNFR1, TNFRSF1A, CD120a, p55) or the 75-kDa type II TNFR (TNFR2, TNFRSF1B, CD120b, p75) activates signaling pathways controlling inflammatory, immune and stress responses, as well as host defense and apoptosis. Multiple studies have investigated the role of TNFRs in the development of early and late renal failure (diabetic nephropathy, nephroangiosclerosis, acute kidney transplant rejection, renal cell carcinoma, glomerulonephritis, sepsis and obstructive renal injury). This article reviews the general characteristics, the analytical aspects and the biology of TNFRs in this domain. In addition, the potential therapeutic application of specific TNFR blockers is discussed.
Topics: Animals; Apoptosis; Carcinoma, Renal Cell; Cell Proliferation; Disease Models, Animal; Humans; Immune System; Inflammation; Kidney Diseases; Kidney Neoplasms; Kidney Transplantation; Mice; Models, Biological; Protein Structure, Tertiary; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Sepsis; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 22965073
DOI: 10.1159/000342333