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Journal of Cellular and Molecular... Aug 2019Obstructive nephropathy is the end result of a variety of diseases that block drainage from the kidney(s). Transforming growth factor-β1 (TGF-β1)/Smad3-driven renal...
Obstructive nephropathy is the end result of a variety of diseases that block drainage from the kidney(s). Transforming growth factor-β1 (TGF-β1)/Smad3-driven renal fibrosis is the common pathogenesis of obstructive nephropathy. In this study, we identified petchiether A (petA), a novel small-molecule meroterpenoid from Ganoderma, as a potential inhibitor of TGF-β1-induced Smad3 phosphorylation. The obstructive nephropathy was induced by unilateral ureteral obstruction (UUO) in mice. Mice received an intraperitoneal injection of petA/vehicle before and after UUO or sham operation. An in vivo study revealed that petA protected against renal inflammation and fibrosis by reducing the infiltration of macrophages, inhibiting the expression of proinflammatory cytokines (interleukin-1β and tumour necrosis factor-α) and reducing extracellular matrix deposition (α-smooth muscle actin, collagen I and fibronectin) in the obstructed kidney of UUO mice; these changes were associated with suppression of Smad3 and NF-κB p65 phosphorylation. Petchiether A inhibited Smad3 phosphorylation in vitro and down-regulated the expression of the fibrotic marker collagen I in TGF-β1-treated renal epithelial cells. Further, we found that petA dose-dependently suppressed Smad3-responsive promoter activity, indicating that petA inhibits gene expression downstream of the TGF-β/Smad3 signalling pathway. In conclusion, our findings suggest that petA protects against renal inflammation and fibrosis by selectively inhibiting TGF-β/Smad3 signalling.
Topics: Actins; Animals; Cell Line; Collagen; Fibronectins; Fibrosis; Humans; Inflammation; Kidney; Kidney Diseases; Male; Mice, Inbred C57BL; NF-kappa B; Phosphorylation; Signal Transduction; Smad3 Protein; Terpenes; Transforming Growth Factor beta; Ureteral Obstruction
PubMed: 31211499
DOI: 10.1111/jcmm.14454 -
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 -
Journal of Nephrology Oct 2019A significant interaction between kidneys and lungs has been shown in physiological and pathological conditions. The two organs can both be targets of the same systemic... (Review)
Review
A significant interaction between kidneys and lungs has been shown in physiological and pathological conditions. The two organs can both be targets of the same systemic disease (eg., some vasculitides). Moreover, loss of normal function of either of them can induce direct and indirect dysregulation of the other one. Subjects suffering from COPD may have systemic inflammation, hypoxemia, endothelial dysfunction, increased sympathetic activation and increased aortic stiffness. As well as the exposure to nicotine, all the foresaid factors can induce a microvascular damage, albuminuria, and a worsening of renal function. Renal failure in COPD can be unrecognized since elderly and frail patients may have normal serum creatinine concentration. Lungs and kidneys participate in maintaining the acid-base balance. Compensatory role of the lungs rapidly expresses through an increase or reduction of ventilation. Renal compensation usually requires a few days as it is achieved through changes in bicarbonate reabsorption. Chronic kidney disease and end-stage renal diseases increase the risk of pneumonia. Vaccination against Streptococcus pneumonia and seasonal influenza is recommended for these patients. Vaccines against the last very virulent H1N1 influenza A strain are also available and effective. Acute lung injury and acute kidney injury are frequent complications in critical illnesses, associated with high morbidity and mortality. The concomitant failure of kidneys and lungs implies a multidisciplinary approach, both in terms of diagnostic processes and therapeutic management.
Topics: Humans; Kidney Diseases; Kidney Failure, Chronic; Lung Diseases; Pulmonary Disease, Chronic Obstructive; Renal Dialysis
PubMed: 30523563
DOI: 10.1007/s40620-018-00563-1 -
Kidney360 Nov 2021Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an under-recognized disorder.
BACKGROUND
Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an under-recognized disorder.
METHODS
Mice with targeted disruption of the molybdenum cofactor sulfurase () gene were generated to enable an integrated understanding of purine disorders and evaluate pathophysiologic functions of this gene which is found in a large number of pathways and is known to be associated with autism.
RESULTS
-deficient mice die with 4 weeks of age due to renal failure of distinct obstructive nephropathy with xanthinuria, xanthine deposits, cystic tubular dilation, Tamm-Horsfall (uromodulin) protein (THP) deposits, tubular cell necrosis with neutrophils, and occasionally hydronephrosis with urolithiasis. Obstructive nephropathy is associated with moderate interstitial inflammatory and fibrotic responses, anemia, reduced detoxification systems, and important alterations of the metabolism of purines, amino acids, and phospholipids. Conversely, heterozygous mice expressing reduced MOCOS protein are healthy with no apparent pathology.
CONCLUSIONS
-deficient mice develop a lethal obstructive nephropathy associated with profound metabolic changes. Studying MOCOS functions may provide important clues about the underlying pathogenesis of xanthinuria and other diseases requiring early diagnosis.
Topics: Animals; Kidney Diseases; Mice; Purine-Pyrimidine Metabolism, Inborn Errors; Urolithiasis; Xanthine; Xanthine Dehydrogenase
PubMed: 35372998
DOI: 10.34067/KID.0001732021 -
Molecular Metabolism May 2023In the fibrotic kidneys, the extent of a formed deleterious microenvironment is determined by cellular mechanical forces. This process requires metabolism for energy....
OBJECTIVE
In the fibrotic kidneys, the extent of a formed deleterious microenvironment is determined by cellular mechanical forces. This process requires metabolism for energy. However, how cellular mechanics and metabolism are connected remains unclear.
METHODS
A multi-disciplinary approach was employed: the fibrotic kidney disease models were induced by renal ischemia-reperfusion injury and unilateral ureteral obstruction in Calponin 2 (CNN2) knockdown mice. Proteomics, bioinformatics, and in vivo and in vitro molecular experimental pathology studies were performed.
RESULT
Our proteomics revealed that actin filament binding and cell metabolism are the two most dysregulated events in the fibrotic kidneys. As a prominent actin stabilizer, CNN2 was predominantly expressed in fibroblasts and pericytes. In CKD patients, CNN2 levels was markedly induced in blood. In mice, CNN2 knockdown preserves kidney function and alleviates fibrosis. Global proteomics profiled that CNN2 knockdown enhanced the activities of the key rate-limiting enzymes and regulators of fatty acid oxidation (FAO) in the diseased kidneys. Inhibiting carnitine palmitoyltransferase 1α in the FAO pathway resulted in lipid accumulation and extracellular matrix deposition in the fibrotic kidneys, which were restored after CNN2 knockdown. Bioinformatics and chromatin immunoprecipitation showed that CNN2 interactor, estrogen receptor 2 (ESR2), binds peroxisome proliferator-activated receptor-α (PPARα) to transcriptionally regulate FAO downstream target genes expression amid kidney fibrosis. In vitro, ESR2 knockdown repressed the mRNA levels of PPARα and the key genes in the FAO pathway. Conversely, activation of PPARα reduced CNN2-induced matrix inductions.
CONCLUSIONS
Our results suggest that balancing cell mechanics and metabolism is crucial to develop therapeutic strategies to halt kidney fibrosis.
Topics: Animals; Mice; Fibrosis; Kidney; Kidney Diseases; PPAR alpha; Calmodulin-Binding Proteins; Calponins
PubMed: 36963615
DOI: 10.1016/j.molmet.2023.101712 -
Journal of Ultrasound in Medicine :... Mar 2021Renal cysts can be focal or diffuse and unilateral or bilateral. In childhood, most renal cysts are due to hereditary diseases rather than simple cysts or acquired... (Review)
Review
Renal cysts can be focal or diffuse and unilateral or bilateral. In childhood, most renal cysts are due to hereditary diseases rather than simple cysts or acquired cystic diseases, unlike adults. Inherited cystic diseases can be ciliopathies due to a primary ciliary defect (as in polycystic kidney diseases and nephronophthisis). Acquired causes include obstructive cystic dysplasia, dyselectrolytemia, and acquired cysts in renal replacement therapy. The final diagnosis requires a multispecialty approach, including radiology, pathology, and genetics. Imaging is a very important component in treating patients with cystic renal diseases. This article discusses the ultrasound findings of cystic renal diseases in children, along with a brief discussion of other imaging modalities and a suggested ultrasound reporting format.
Topics: Adult; Child; Cysts; Humans; Kidney Diseases, Cystic; Kidney Neoplasms; Polycystic Kidney, Autosomal Recessive; Ultrasonography
PubMed: 32798245
DOI: 10.1002/jum.15435 -
Free Radical Biology & Medicine Aug 2022Renal tubulointerstitial fibrosis is the hallmark of chronic kidney disease (CKD) and the best predictor of renal survival. However, current treatments for CKD remain...
Renal tubulointerstitial fibrosis is the hallmark of chronic kidney disease (CKD) and the best predictor of renal survival. However, current treatments for CKD remain extremely limited. Therefore, novel therapeutic targets are urgently needed to either stop or reverse CKD progression. The present study was designed to explore the potential role of GPR87, a member of the G protein-coupled receptors (GPCRs) family, in the pathogenesis of tubulointerstitial fibrosis. It was found that GPR87 was significantly induced in the kidney, especially in tubular areas, from different mouse models of renal fibrosis, including unilateral ureteral obstruction (UUO) nephropathy, aristolochic acid nephropathy, and diabetic nephropathy, respectively. Tubule-specific GPR87 deletion dramatically ameliorated tubulointerstitial fibrosis in UUO mice. Mechanistically, GPR87 accelerated glycolysis and mitochondrial injury by YAP-hexokinase-2 signaling, thereby promoting renal fibrosis. Importantly, the upregulation of GPR87 was also found in the kidney from patients with various CKD, indicating that the induction of GPR87 may be a common feature of human kidney diseases. Collectively, our studies for the first time demonstrate that GPR87 plays a pivotal role in renal fibrosis at least in part by accelerating glycolysis and mitochondrial injury, suggesting that targeting GPR87 may represent a novel therapeutic strategy for patients with CKD.
Topics: Animals; Diabetic Nephropathies; Fibrosis; Glycolysis; Humans; Kidney; Kidney Diseases; Mice; Mice, Inbred C57BL; Receptors, Lysophosphatidic Acid; Renal Insufficiency, Chronic; Ureteral Obstruction
PubMed: 35843477
DOI: 10.1016/j.freeradbiomed.2022.07.004 -
Cell Death & Disease May 2022Whether metabolites derived from injured renal tubular epithelial cells (TECs) participate in renal fibrosis is poorly explored. After TEC injury, various metabolites...
Whether metabolites derived from injured renal tubular epithelial cells (TECs) participate in renal fibrosis is poorly explored. After TEC injury, various metabolites are released and among the most potent is adenosine triphosphate (ATP), which is released via ATP-permeable channels. In these hemichannels, connexin 43 (Cx43) is the most common member. However, its role in renal interstitial fibrosis (RIF) has not been fully examined. We analyzed renal samples from patients with obstructive nephropathy and mice with unilateral ureteral obstruction (UUO). Cx43-KSP mice were generated to deplete Cx43 in TECs. Through transcriptomics, metabolomics, and single-cell sequencing multi-omics analysis, the relationship among tubular Cx43, ATP, and macrophages in renal fibrosis was explored. The expression of Cx43 in TECs was upregulated in both patients and mice with obstructive nephropathy. Knockdown of Cx43 in TECs or using Cx43-specific inhibitors reduced UUO-induced inflammation and fibrosis in mice. Single-cell RNA sequencing showed that ATP specific receptors, including P2rx4 and P2rx7, were distributed mainly on macrophages. We found that P2rx4- or P2rx7-positive macrophages underwent pyroptosis after UUO, and in vitro ATP directly induced pyroptosis by macrophages. The administration of P2 receptor or P2X7 receptor blockers to UUO mice inhibited macrophage pyroptosis and demonstrated a similar degree of renoprotection as Cx43 genetic depletion. Further, we found that GAP 26 (a Cx43 hemichannel inhibitor) and A-839977 (an inhibitor of the pyroptosis receptor) alleviated UUO-induced fibrosis, while BzATP (the agonist of pyroptosis receptor) exacerbated fibrosis. Single-cell sequencing demonstrated that the pyroptotic macrophages upregulated the release of CXCL10, which activated intrarenal fibroblasts. Cx43 mediates the release of ATP from TECs during renal injury, inducing peritubular macrophage pyroptosis, which subsequently leads to the release of CXCL10 and activation of intrarenal fibroblasts and acceleration of renal fibrosis.
Topics: Adenosine Triphosphate; Animals; Connexin 43; Epithelial Cells; Fibrosis; Humans; Kidney Diseases; Mice; Ureteral Obstruction
PubMed: 35641484
DOI: 10.1038/s41419-022-04910-w -
EMBO Molecular Medicine Mar 2020Kidney fibrosis is characterized by expansion and activation of platelet-derived growth factor receptor-β (PDGFR-β)-positive mesenchymal cells. To study the...
Kidney fibrosis is characterized by expansion and activation of platelet-derived growth factor receptor-β (PDGFR-β)-positive mesenchymal cells. To study the consequences of PDGFR-β activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR-β activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch toward myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis, and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts. Fibrosis induced secondary tubular epithelial injury at later stages, coinciding with microinflammation, and aggravated the progression of hypertensive and obstructive nephropathy. Inhibition of PDGFR activation reversed fibrosis more effectively in the tubulointerstitium compared to glomeruli. Gene expression signatures in mice with PDGFR-β activation resembled those found in patients. In conclusion, PDGFR-β activation alone is sufficient to induce progressive renal fibrosis and failure, mimicking key aspects of chronic kidney disease in humans. Our data provide direct proof that fibrosis per se can drive chronic organ damage and establish a model of primary fibrosis allowing specific studies targeting fibrosis progression and regression.
Topics: Animals; Fibroblasts; Fibrosis; Humans; Kidney; Kidney Diseases; Mice; Mice, Transgenic; Myofibroblasts; Receptor, Platelet-Derived Growth Factor beta
PubMed: 31943786
DOI: 10.15252/emmm.201911021 -
Pediatric Nephrology (Berlin, Germany) Oct 2020
Topics: Biomarkers; Child; Humans; Kidney; Kidney Diseases; Urinary Tract
PubMed: 32638086
DOI: 10.1007/s00467-020-04677-2