-
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 -
Current Opinion in Nephrology and... Jan 2015To review the role of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling in the progression of chronic kidney diseases. (Review)
Review
PURPOSE OF REVIEW
To review the role of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling in the progression of chronic kidney diseases.
RECENT FINDINGS
The JAK-STAT pathway transmits signals from extracellular ligands, including many cytokines and chemokines. While these responses are best characterized in lymphoid cells, they also occur in kidney cells such as podocytes, mesangial cells, and tubular cells. JAK-STAT expression and signaling abnormalities occur in humans and animal models of different chronic kidney diseases. Enhanced expression and augmented activity of JAK1, JAK2, and STAT3 promote diabetic nephropathy and their inhibition appears to reduce the disease. Activation of JAK-STAT signaling in autosomal dominant polycystic kidney disease may play an important role in cyst growth. Activation of JAK-STAT signaling promotes HIV-associated nephropathy and may also participate in the tubular responses to chronic obstructive uropathy. On the basis of data from experimental models, inhibition of JAK-STAT signaling, via increased expression of the suppressors of cytokine signaling proteins or pharmacologic inhibition of JAK and STAT proteins, could play a therapeutic role in multiple chronic kidney diseases.
SUMMARY
Activation of the JAK-STAT pathway appears to play a role in the progression of some chronic kidney diseases. More work is needed to determine the specific role the pathway plays in individual diseases.
Topics: Diabetic Nephropathies; Humans; Janus Kinases; Kidney Diseases; STAT Transcription Factors; Signal Transduction
PubMed: 25415616
DOI: 10.1097/MNH.0000000000000079 -
World Journal of Gastroenterology Jun 2012Acute kidney injury (AKI), defined as an abrupt increase in the serum creatinine level by at least 0.3 mg/dL, occurs in about 20% of patients hospitalized for... (Review)
Review
Acute kidney injury (AKI), defined as an abrupt increase in the serum creatinine level by at least 0.3 mg/dL, occurs in about 20% of patients hospitalized for decompensating liver cirrhosis. Patients with cirrhosis are susceptible to developing AKI because of the progressive vasodilatory state, reduced effective blood volume and stimulation of vasoconstrictor hormones. The most common causes of AKI in cirrhosis are pre-renal azotemia, hepatorenal syndrome and acute tubular necrosis. Differential diagnosis is based on analysis of circumstances of AKI development, natriuresis, urine osmolality, response to withdrawal of diuretics and volume repletion, and rarely on renal biopsy. Chronic glomerulonephritis and obstructive uropathy are rare causes of azotemia in cirrhotic patients. AKI is one of the last events in the natural history of chronic liver disease, therefore, such patients should have an expedited referral for liver transplantation. Hepatorenal syndrome (HRS) is initiated by progressive portal hypertension, and may be prematurely triggered by bacterial infections, nonbacterial systemic inflammatory reactions, excessive diuresis, gastrointestinal hemorrhage, diarrhea or nephrotoxic agents. Each type of renal disease has a specific treatment approach ranging from repletion of the vascular system to renal replacement therapy. The treatment of choice in type 1 hepatorenal syndrome is a combination of vasoconstrictor with albumin infusion, which is effective in about 50% of patients. The second-line treatment of HRS involves a transjugular intrahepatic portosystemic shunt, renal vasoprotection or systems of artificial liver support.
Topics: Acute Kidney Injury; Biomarkers; Chronic Disease; Creatinine; Hepatorenal Syndrome; Humans; Hypertension, Portal; Kidney; Kidney Diseases; Liver Cirrhosis; Liver Transplantation; Prognosis; Renal Insufficiency; Risk Factors; Up-Regulation
PubMed: 22791939
DOI: 10.3748/wjg.v18.i24.3035 -
Cellular and Molecular Life Sciences :... Aug 2022p53 is a major regulator of cell cycle arrest, apoptosis, and senescence. While involvement of p53 in tumorigenesis is well established, recent studies implicate p53 in... (Review)
Review
p53 is a major regulator of cell cycle arrest, apoptosis, and senescence. While involvement of p53 in tumorigenesis is well established, recent studies implicate p53 in the initiation and progression of several renal diseases, which is the focus of this review. Ischemic-, aristolochic acid (AA) -, diabetic-, HIV-associated-, obstructive- and podocyte-induced nephropathies are accompanied by activation and/or elevated expression of p53. Studies utilizing chemical or renal-specific inhibition of p53 in mice confirm the pathogenic role of this transcription factor in acute kidney injury and chronic kidney disease. TGF-β1, NOX, ATM/ATR kinases, Cyclin G, HIPK, MDM2 and certain micro-RNAs are important determinants of renal p53 function in response to trauma. AA, cisplatin or TGF-β1-mediated ROS generation via NOXs promotes p53 phosphorylation and subsequent tubular dysfunction. p53-SMAD3 transcriptional cooperation downstream of TGF-β1 orchestrates induction of fibrotic factors, extracellular matrix accumulation and pathogenic renal cell communication. TGF-β1-induced micro-RNAs (such as mir-192) could facilitate p53 activation, leading to renal hypertrophy and matrix expansion in response to diabetic insults while AA-mediated mir-192 induction regulates p53 dependent epithelial G/M arrest. The widespread involvement of p53 in tubular maladaptive repair, interstitial fibrosis, and podocyte injury indicate that p53 clinical targeting may hold promise as a novel therapeutic strategy for halting progression of certain acute and chronic renal diseases, which affect hundreds of million people worldwide.
Topics: Animals; Fibrosis; Humans; Kidney; Kidney Diseases; Mice; Renal Insufficiency, Chronic; Signal Transduction; Transforming Growth Factor beta1; Tumor Suppressor Protein p53
PubMed: 35941392
DOI: 10.1007/s00018-022-04505-w -
Journal of Cellular and Molecular... Feb 2019SUMOylation of proteins is an important regulatory element in modulating protein function and has been implicated in the pathogenesis of numerous human diseases such as... (Review)
Review
SUMOylation of proteins is an important regulatory element in modulating protein function and has been implicated in the pathogenesis of numerous human diseases such as cancers, neurodegenerative diseases, brain injuries, diabetes, and familial dilated cardiomyopathy. Growing evidence has pointed to a significant role of SUMO in kidney diseases such as DN, RCC, nephritis, AKI, hypertonic stress and nephrolithiasis. Recently, emerging studies in podocytes demonstrated that SUMO might have a protective role against podocyte apoptosis. However, the SUMO code responsible for beneficial outcome in the kidney remains to be decrypted. Our recent experiments have revealed that the expression of both SUMO and SUMOylated proteins is appreciably elevated in hypoxia-induced tubular epithelial cells (TECs) as well as in the unilateral ureteric obstruction (UUO) mouse model, suggesting a role of SUMO in TECs injury and renal fibrosis. In this review, we attempt to decipher the SUMO code in the development of kidney diseases by summarizing the defined function of SUMO and looking forward to the potential role of SUMO in kidney diseases, especially in the pathology of renal fibrosis and CKD, with the goal of developing strategies that maximize correct interpretation in clinical therapy and prognosis.
Topics: Acute Kidney Injury; Apoptosis; Carcinoma, Renal Cell; Diabetic Nephropathies; Fibrosis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Neoplasms; Nephritis; Nephrolithiasis; Podocytes; Protein Processing, Post-Translational; Smad Proteins; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Transforming Growth Factor beta; Ureteral Obstruction
PubMed: 30506859
DOI: 10.1111/jcmm.14021 -
Kidney International Apr 2004
Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Humans; Kidney; Kidney Diseases; Male; Proteinuria; Ureteral Obstruction
PubMed: 15086496
DOI: 10.1111/j.1523-1755.2004.00533.x -
Kidney International May 2024Desmosomes are multi-protein cell-cell adhesion structures supporting cell stability and mechanical stress resilience of tissues, best described in skin and heart. The...
Desmosomes are multi-protein cell-cell adhesion structures supporting cell stability and mechanical stress resilience of tissues, best described in skin and heart. The kidney is exposed to various mechanical stimuli and stress, yet little is known about kidney desmosomes. In healthy kidneys, we found desmosomal proteins located at the apical-junctional complex in tubular epithelial cells. In four different animal models and patient biopsies with various kidney diseases, desmosomal components were significantly upregulated and partly miss-localized outside of the apical-junctional complexes along the whole lateral tubular epithelial cell membrane. The most upregulated component was desmoglein-2 (Dsg2). Mice with constitutive tubular epithelial cell-specific deletion of Dsg2 developed normally, and other desmosomal components were not altered in these mice. When challenged with different types of tubular epithelial cell injury (unilateral ureteral obstruction, ischemia-reperfusion, and 2,8-dihydroxyadenine crystal nephropathy), we found increased tubular epithelial cell apoptosis, proliferation, tubular atrophy, and inflammation compared to wild-type mice in all models and time points. In vitro, silencing DSG2 via siRNA weakened cell-cell adhesion in HK-2 cells and increased cell death. Thus, our data show a prominent upregulation of desmosomal components in tubular cells across species and diseases and suggest a protective role of Dsg2 against various injurious stimuli.
Topics: Animals; Humans; Mice; Cell Adhesion; Desmoglein 2; Desmosomes; Heart; Kidney Diseases
PubMed: 38395410
DOI: 10.1016/j.kint.2024.01.037 -
Nephron 2016Animal models are essential tools to understand the mechanisms underlying the development and progression of renal disease and to study potential therapeutic approaches.... (Review)
Review
Animal models are essential tools to understand the mechanisms underlying the development and progression of renal disease and to study potential therapeutic approaches. Recently, interventional models suitable to induce acute and chronic kidney disease in the mouse have become a focus of interest due to the wide availability of genetically engineered mouse lines. These models differ by their damaging mechanism (cell toxicity, immune mechanisms, surgical renal mass reduction, ischemia, hypertension, ureter obstruction etc.), functional and histomorphological phenotype and disease evolution. The susceptibility to a damaging mechanism often depends on strain and gender. The C57BL/6 strain, the most commonly used genetic background of transgenic mice, appears to be relatively resistant against developing glomerulosclerosis, proteinuria and hypertension. This review serves to provide a comprehensive overview of interventional mouse models of acute and chronic kidney disease.
Topics: Animals; Disease Models, Animal; Genetic Predisposition to Disease; Kidney Diseases; Mice
PubMed: 27212380
DOI: 10.1159/000445171 -
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 -
The association of obstructive sleep apnea and renal outcomes-a systematic review and meta-analysis.BMC Nephrology Oct 2017The aim of this systematic review and meta-analysis was to summarize the association of obstructive sleep apnea (OSA) with renal outcome. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The aim of this systematic review and meta-analysis was to summarize the association of obstructive sleep apnea (OSA) with renal outcome.
METHODS
Our study followed the PRISMA guidelines. Two independent reviewers searched for relevant articles in the databases of Pubmed, the Web of Science and CENTRAL, and conducted study selection and quality assessment. A random-effect model was used to estimate the effects.
RESULTS
total of 1240 articles were initially identified (Pubmed = 568, Web of Science = 640, CENTRAL = 32). After removal of duplicate articles (n = 415) and irrelevant articles (n = 788), 37 were selected for full-text review, and 18 were finally included in the analysis. Overall, patients diagnosed with OSA were found to have a higher odds ratio (OR) of a poorer renal outcome, with a pooled OR of 1.77 (95% C.I.: 1.37–2.29). The significant association between OSA and a poorer renal outcome was not affected by the medical condition of diabetes mellitus (DM). In addition, we found that OSA was consistently associated with higher albuminuria/proteinuria and a lower estimated glomerular filtration rate (eGFR), with a pooled OR of 1.84 (95% C.I.: 1.24–2.73) and 1.60 (95% C.I.: 1.19–2.16), respectively. A greater OSA severity was also found to be related to a higher OR, with a mild group OR of 1.45 (95% C.I.: 1.19–1.77) and a moderate and severe group OR of 2.39 (95% C.I.: 1.96–2.90).
CONCLUSIONS
Our study demonstrated that OSA is significantly associated with poorer renal function.
Topics: Cross-Sectional Studies; Humans; Kidney; Kidney Diseases; Risk Factors; Sleep Apnea, Obstructive
PubMed: 29037156
DOI: 10.1186/s12882-017-0731-2