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DNASE1L3 is an extracellular nuclease that digests chromatin released from apoptotic cells. DNASE1L3 mutations impair the enzyme function, enhance autoantibody production and type I interferon (IFN-I) responses, and cause different autosomal recessive phenotypes ranging from hypocomplementemic urticarial vasculitis syndrome to full-blown systemic lupus erythematosus (SLE). Kidney involvement in patients with DNASE1L3 mutations is poorly characterised. Herein, we describe the clinical course of three children with monogenic SLE due to DNASE1L3 mutations who developed refractory glomerulonephritis leading to kidney failure. They had different renal histopathological patterns (i.e., membranous, endo- and extra-capillary glomerulonephritis and thrombotic microangiopathy), all belonging to the lupus nephritis (LN) spectrum. One patient had a mixed phenotype, showing an overlap between SLE and ANCA-associated vasculitis. Using immunofluorescence, we detected glomerular expression of the IFN I-induced human myxovirus resistance protein 1 (MXA), which was particularly evident in glomerular endothelial cells. 2/3 patients had increased expression of interferon-stimulated genes in the peripheral blood and all three patients had reduced serum DNAse activity. Our findings suggest that DNASE1L3-related glomerulonephritis can be included in the spectrum of IFN I-mediated kidney disorders, and provide the rationale for IFN I-directed therapies in order to improve the poor outcome of this rare condition.
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SIGNIFICANCE STATEMENT: We hypothesized that triple therapy with inhibitors of the renin-angiotensin system (RAS), sodium-glucose transporter (SGLT)-2, and the mineralocorticoid receptor (MR) would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression in Col4a3 -deficient mice, a model of Alport syndrome. Late-onset ramipril monotherapy or dual ramipril/empagliflozin therapy attenuated CKD and prolonged overall survival by 2 weeks. Adding the nonsteroidal MR antagonist finerenone extended survival by 4 weeks. Pathomics and RNA sequencing revealed significant protective effects on the tubulointerstitium when adding finerenone to RAS/SGLT2 inhibition. Thus, triple RAS/SGLT2/MR blockade has synergistic effects and might attenuate CKD progression in patients with Alport syndrome and possibly other progressive chronic kidney disorders. BACKGROUND: Dual inhibition of the renin-angiotensin system (RAS) plus sodium-glucose transporter (SGLT)-2 or the mineralocorticoid receptor (MR) demonstrated additive renoprotective effects in large clinical trials. We hypothesized that triple therapy with RAS/SGLT2/MR inhibitors would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression. METHODS: We performed a preclinical randomized controlled trial (PCTE0000266) in Col4a3 -deficient mice with established Alport nephropathy. Treatment was initiated late (age 6 weeks) in mice with elevated serum creatinine and albuminuria and with glomerulosclerosis, interstitial fibrosis, and tubular atrophy. We block-randomized 40 male and 40 female mice to either nil (vehicle) or late-onset food admixes of ramipril monotherapy (10 mg/kg), ramipril plus empagliflozin (30 mg/kg), or ramipril plus empagliflozin plus finerenone (10 mg/kg). Primary end point was mean survival. RESULTS: Mean survival was 63.7±10.0 days (vehicle), 77.3±5.3 days (ramipril), 80.3±11.0 days (dual), and 103.1±20.3 days (triple). Sex did not affect outcome. Histopathology, pathomics, and RNA sequencing revealed that finerenone mainly suppressed the residual interstitial inflammation and fibrosis despite dual RAS/SGLT2 inhibition. CONCLUSION: Experiments in mice suggest that triple RAS/SGLT2/MR blockade may substantially improve renal outcomes in Alport syndrome and possibly other progressive CKDs because of synergistic effects on the glomerular and tubulointerstitial compartments.
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Diabetes Mellitus Tipo 2 , Nefrite Hereditária , Insuficiência Renal Crônica , Animais , Feminino , Masculino , Camundongos , Anti-Hipertensivos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fibrose , Proteínas Facilitadoras de Transporte de Glucose/farmacologia , Proteínas Facilitadoras de Transporte de Glucose/uso terapêutico , Nefrite Hereditária/tratamento farmacológico , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Ramipril/uso terapêutico , Receptores de Mineralocorticoides , Insuficiência Renal Crônica/tratamento farmacológico , Sistema Renina-Angiotensina , Sódio , Transportador 2 de Glucose-Sódio/farmacologia , Transportador 2 de Glucose-Sódio/uso terapêuticoRESUMO
Polyploidization of tubular cells (TC) is triggered by acute kidney injury (AKI) to allow survival in the early phase after AKI, but in the long run promotes fibrosis and AKI-chronic kidney disease (CKD) transition. The molecular mechanism governing the link between polyploid TC and kidney fibrosis remains to be clarified. In this study, we demonstrate that immediately after AKI, expression of cell cycle markers mostly identifies a population of DNA-damaged polyploid TC. Using transgenic mouse models and single-cell RNA sequencing we show that, unlike diploid TC, polyploid TC accumulate DNA damage and survive, eventually resting in the G1 phase of the cell cycle. In vivo and in vitro single-cell RNA sequencing along with sorting of polyploid TC shows that these cells acquire a profibrotic phenotype culminating in transforming growth factor (TGF)-ß1 expression and that TGF-ß1 directly promotes polyploidization. This demonstrates that TC polyploidization is a self-sustained mechanism. Interactome analysis by single-cell RNA sequencing revealed that TGF-ß1 signaling fosters a reciprocal activation loop among polyploid TC, macrophages, and fibroblasts to sustain kidney fibrosis and promote CKD progression. Collectively, this study contributes to the ongoing revision of the paradigm of kidney tubule response to AKI, supporting the existence of a tubulointerstitial cross talk mediated by TGF-ß1 signaling produced by polyploid TC following DNA damage.NEW & NOTEWORTHY Polyploidization in tubular epithelial cells has been neglected until recently. Here, we showed that polyploidization is a self-sustained mechanism that plays an important role during chronic kidney disease development, proving the existence of a cross talk between infiltrating cells and polyploid tubular cells. This study contributes to the ongoing revision of kidney adaptation to injury, posing polyploid tubular cells at the center of the process.
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Injúria Renal Aguda , Fator de Crescimento Transformador beta1 , Animais , Camundongos , Fator de Crescimento Transformador beta1/genética , Injúria Renal Aguda/genética , Células Epiteliais , Poliploidia , FibroseRESUMO
Chronic kidney disease (CKD) is a constantly growing global health burden, with more than 840 million people affected worldwide. CKD presents sex disparities in the pathophysiology of the disease, as well as in the epidemiology, clinical manifestations, and disease progression. Overall, while CKD is more frequent in females, males have a higher risk to progress to end-stage kidney disease. In recent years, numerous studies have highlighted the role of sex hormones in the health and diseases of several organs, including the kidney. In this review, we present a clinical overview of the sex-differences in CKD and a selection of prominent kidney diseases causing CKD: lupus nephritis, diabetic kidney disease, IgA nephropathy, and autosomal dominant polycystic kidney disease. We report clinical and experimental findings on the role of sex hormones in the development of the disease and its progression to end-stage kidney disease.
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Nefropatias Diabéticas , Falência Renal Crônica , Insuficiência Renal Crônica , Masculino , Feminino , Humanos , Rim , Insuficiência Renal Crônica/epidemiologia , Nefropatias Diabéticas/epidemiologia , Hormônios Esteroides Gonadais , Progressão da DoençaRESUMO
Aicardi-Goutières syndrome (AGS) is a well-characterized monogenic type I interferonopathy presenting with prominent neurologic manifestations. Among extraneurologic features, renal involvement has been described in only 1 patient with an IFIH1 mutation in whom membranous nephropathy developed. The pathogenic role of augmented interferon (IFN) signaling in tissues other than the central nervous system remains to be elucidated. We report a case of collapsing glomerulopathy in a 15-year-old girl affected by AGS with RNASEH2B mutation (an alanine-to-threonine change at amino acid 177), which led to kidney failure. The patient had no lupus-like features and lacked the APOL1 G1 and G2 risk alleles. Kidney biopsy showed findings consistent with collapsing glomerulopathy. MxA, a protein involved in antiviral immunity and induced by type I IFNs, was selectively expressed in CD133-positive parietal epithelial cells (PECs) but not in podocytes that stained for synaptopodin or in other glomerular cells. MxA also colocalized within pseudocrescents with CD44, a marker of PEC activation involved in cellular proliferation, differentiation, and migration and in glomerular scarring. Our findings suggest that collapsing glomerulopathy can be a complication of the type I interferonopathy AGS and that a constitutively enhanced type I IFN response in CD133-positive PECs can drive collapsing glomerulopathy.
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Doenças Autoimunes do Sistema Nervoso , Interferon Tipo I , Malformações do Sistema Nervoso , Adolescente , Apolipoproteína L1 , Doenças Autoimunes do Sistema Nervoso/genética , Feminino , Humanos , Glomérulos Renais , Malformações do Sistema Nervoso/genéticaRESUMO
The important achievements in kidney physiological and pathophysiological mechanisms can largely be ascribed to progress in the technology of microscopy. Much of what we know about the architecture of the kidney is based on the fundamental descriptions of anatomic microscopists using light microscopy and later by ultrastructural analysis provided by electron microscopy. These two techniques were used for the first classification systems of kidney diseases and for their constant updates. More recently, a series of novel imaging techniques added the analysis in further dimensions of time and space. Confocal microscopy allowed us to sequentially visualize optical sections along the z-axis and the availability of specific analysis software provided a three-dimensional rendering of thicker tissue specimens. Multiphoton microscopy permitted us to simultaneously investigate kidney function and structure in real time. Fluorescence-lifetime imaging microscopy allowed to study the spatial distribution of metabolites. Super-resolution microscopy increased sensitivity and resolution up to nanoscale levels. With cryo-electron microscopy, researchers could visualize the individual biomolecules at atomic levels directly in the tissues and understand their interaction at subcellular levels. Finally, matrix-assisted laser desorption/ionization imaging mass spectrometry permitted the measuring of hundreds of different molecules at the same time on tissue sections at high resolution. This review provides an overview of available kidney imaging strategies, with a focus on the possible impact of the most recent technical improvements.
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Microscopia Crioeletrônica/métodos , Processamento de Imagem Assistida por Computador/métodos , Nefropatias/diagnóstico por imagem , Rim/diagnóstico por imagem , Microscopia de Fluorescência/métodos , Imagem Molecular/métodos , Animais , Humanos , Rim/citologia , Rim/metabolismo , Nefropatias/metabolismo , Nefropatias/patologia , SoftwareRESUMO
BACKGROUND: Progression of CKD in type 2 diabetes, despite dual inhibition of sodium-glucose transporter-2 and the renin-angiotensin system, remains a concern. Bromoindirubin-3'-oxime (BIO), previously reported to promote podocyte survival and regeneration, is a candidate additional drug to elicit renoprotective effects beyond therapy with metformin, ramipril, and empagliflozin (MRE). Evaluating a drug with standard therapeutics more closely mimics the clinical setting than evaluating the drug alone. METHODS: Uninephrectomized BKS-Lepr-/- (db/db) mice treated with or without MRE served as a model of progressive CKD in type 2 diabetes. Mice on or off MRE were randomized to only 4 weeks of add-on BIO or vehicle. The primary end point was slope of GFR (ΔGFR). RESULTS: Four weeks of MRE treatment alone did not affect ΔGFR, but significantly attenuated hyperglycemia, albuminuria, and glomerulosclerosis and increased podocyte filtration slit density, as assessed by STED super-resolution microscopy upon tissue clearing. BIO alone improved albuminuria, podocyte density in superficial and juxtamedullary nephrons, and podocyte filtration slit density. MRE+BIO combination therapy had additive protective effects on ΔGFR, glomerulosclerosis, podocyte density in juxtamedullary nephrons, and filtration slit density. CONCLUSIONS: Add-on treatment with BIO for only 4 weeks attenuates progression of CKD beyond MRE therapy in mice with type 2 diabetes. Additional drug combinations may help to further delay ESKD in type 2 diabetes.
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Compostos Benzidrílicos/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Glucosídeos/administração & dosagem , Indóis/uso terapêutico , Metformina/administração & dosagem , Oximas/uso terapêutico , Ramipril/administração & dosagem , Animais , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Quimioterapia Combinada , Taxa de Filtração Glomerular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Rim/efeitos dos fármacos , Camundongos , Podócitos/efeitos dos fármacosRESUMO
Acute kidney injury (AKI) is characterized by a rapid deterioration of kidney function, representing a global healthcare concern. In addition, AKI survivors frequently develop chronic kidney disease (CKD), contributing to a substantial proportion of disease burden globally. Yet, over the past 30 years, the burden of CKD has not declined to the same extent as many other important non-communicable diseases, implying a substantial deficit in the understanding of the disease progression. The assumption that the kidney response to AKI is based on a high proliferative potential of proximal tubular cells (PTC) caused a critical confounding factor, which has led to a limited development of strategies to prevent AKI and halt progression toward CKD. In this review, we discuss the latest findings on multiple mechanisms of response related to cell cycle behavior of PTC upon AKI, with a specific focus on their biological relevance. Collectively, we aim to (1) provide a new perspective on interpreting cell cycle progression of PTC in response to damage and (2) discuss how this knowledge can be used to choose the right therapeutic window of treatment for preserving kidney function while avoiding CKD progression.
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Injúria Renal Aguda/patologia , Túbulos Renais/patologia , Insuficiência Renal Crônica/prevenção & controle , Animais , Ciclo Celular , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem da Célula , Inibidores de Histona Desacetilases/farmacologia , Humanos , Mitose , Terapia de Alvo Molecular/métodosRESUMO
Insufficient podocyte regeneration after injury is a central pathomechanism of glomerulosclerosis and chronic kidney disease. Podocytes constitutively secrete the chemokine CXCL12, which is known to regulate homing and activation of stem cells; hence we hypothesized a similar effect of CXCL12 on podocyte progenitors. CXCL12 blockade increased podocyte numbers and attenuated proteinuria in mice with Adriamycin-induced nephropathy. Similar studies in lineage-tracing mice revealed enhanced de novo podocyte formation from parietal epithelial cells in the setting of CXCL12 blockade. Super-resolution microscopy documented full integration of these progenitor-derived podocytes into the glomerular filtration barrier, interdigitating with tertiary foot processes of neighboring podocytes. Quantitative 3D analysis revealed that conventional 2D analysis underestimated the numbers of progenitor-derived podocytes. The 3D analysis also demonstrated differences between juxtamedullary and cortical nephrons in both progenitor endowment and Adriamycin-induced podocyte loss, with more robust podocyte regeneration in cortical nephrons with CXCL12 blockade. Finally, we found that delayed CXCL12 inhibition still had protective effects. In vitro studies found that CXCL12 inhibition uncoupled Notch signaling in podocyte progenitors. These data suggest that CXCL12-driven podocyte-progenitor feedback maintains progenitor quiescence during homeostasis, but also limits their intrinsic capacity to regenerate lost podocytes, especially in cortical nephrons. CXCL12 inhibition could be an innovative therapeutic strategy in glomerular disorders.
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Aptâmeros de Nucleotídeos/farmacologia , Quimiocina CXCL12/antagonistas & inibidores , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Regeneração/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Animais , Aptâmeros de Nucleotídeos/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CXCL12/metabolismo , Modelos Animais de Doenças , Doxorrubicina/toxicidade , Retroalimentação Fisiológica/efeitos dos fármacos , Glomerulosclerose Segmentar e Focal/induzido quimicamente , Glomerulosclerose Segmentar e Focal/complicações , Humanos , Imageamento Tridimensional , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Confocal/métodos , Podócitos/efeitos dos fármacos , Podócitos/patologia , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , Células-Tronco/fisiologia , Resultado do TratamentoRESUMO
Background: Low-voltage area (LVA) ablation, in addition to pulmonary vein isolation (PVI), has been proposed as a new strategy in patients with atrial fibrillation (AF), but clinical trials have shown conflicting results. We performed a systematic review and meta-analysis to assess the impact of LVA ablation in patient undergoing AF ablation (PROSPERO-registered CRD42024537696). Methods: Randomized clinical trials investigating the role of LVA ablation in addition to PVI in patients with AF were searched on PubMed, Embase, and the Cochrane Library from inception to 22 April 2024. Primary outcome was atrial arrhythmia recurrence after the first AF ablation procedure. Secondary endpoints included procedure time, fluoroscopy time, and procedure-related complication rate. Sensitivity analysis including only patients with LVA demonstration at mapping and multiple subgroups analyses were also performed. Results: 1547 patients from 7 studies were included. LVA ablation in addition to PVI reduced atrial arrhythmia recurrence (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.52-0.81, p < 0.001) with a number needed to treat to prevent recurrence of 10. No difference in procedure time (mean difference [MD] -5.32 min, 95% CI -19.01-8.46 min, p = 0.45), fluoroscopy time (MD -1.10 min, 95% CI -2.48-0.28 min, p = 0.12) and complication rate (OR 0.81, 95% CI 0.40-1.61, p = 0.54) was observed. Consistent results were demonstrated when considering only patients with LVA during mapping and in prespecified subgroups for AF type (paroxysmal vs. persistent), multicentric vs. monocentric trial, and ablation strategy in control group. Conclusions: In patients with AF, ablation of LVAs in addition to PVI reduces atrial arrhythmia recurrence without a significant increase in procedure time, fluoroscopy time, or complication rate.
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Neuropsychiatric disorders are common manifestations in 22q11.2 deletion syndrome (22q11.2DS-DiGeorge Syndrome). Although many patients with 22q11.2DS receive antipsychotic treatment for psychotic disorders, little is known about the safety and tolerability of antipsychotics in 22q11.2DS and resistant psychosis. The aim of this case series is to describe the effectiveness as well as safety and tolerability profile coming from the real-world observation of three clinical cases affected by 22q11.2DS and treatment-resistant psychosis. We administered the following tests: the Columbia Suicide Severity Rating Scale, the Hamilton Rating Scale for Anxiety, the Positive and Negative Severity Scale, the Clinical Global Impression-Severity Scale, the Yale-Brown Obsessive-Compulsive Scale, the Beck Depression Inventory and the Beck Hopelessness Scale. All these questionnaires were administered at the first visit (T0), and then 3 (T1) 6 (T2) and 12 months after (T3). We observed a clinical improvement that remained stable at 12 months. Furthermore, in our patients, the clinical effectiveness was achieved with a very low dose of clozapine (<150â mg/day) concerning the standard dose used in idiopathic schizophrenia (>300â mg/day to 600â mg/day).
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Kidney diseases are a global health concern. Modeling of kidney disease for translational research is often challenging because of species specificities or the postmitotic status of kidney epithelial cells that make primary cultures, for example podocytes. Here, we report a protocol for preparing primary cultures of podocytes based on the isolation and in vitro propagation of immature kidney progenitor cells subsequently differentiated into mature podocytes. This protocol can be useful for studying physiology and pathophysiology of human kidney progenitors and to obtain differentiated podocytes for modeling podocytopathies and other kidney disorders involving podocytes.
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Background: The NLRP3 inflammasome integrates several danger signals into the activation of innate immunity and inflammation by secreting IL-1ß and IL-18. Most published data relate to the NLRP3 inflammasome in immune cells, but some reports claim similar roles in parenchymal, namely epithelial, cells. For example, podocytes, epithelial cells critical for the maintenance of kidney filtration, have been reported to express NLRP3 and to release IL-ß in diabetic kidney disease, contributing to filtration barrier dysfunction and kidney injury. We questioned this and hence performed independent verification experiments. Methods: We studied the expression of inflammasome components in human and mouse kidneys and human podocytes using single-cell transcriptome analysis. Human podocytes were exposed to NLRP3 inflammasome agonists in vitro and we induced diabetes in mice with a podocyte-specific expression of the Muckle-Wells variant of NLRP3, leading to overactivation of the Nlrp3 inflammasome (Nphs2Cre;Nlrp3A350V) versus wildtype controls. Phenotype analysis included deep learning-based glomerular and podocyte morphometry, tissue clearing, and STED microscopy of the glomerular filtration barrier. The Nlrp3 inflammasome was blocked by feeding ß-hydroxy-butyrate. Results: Single-cell transcriptome analysis did not support relevant NLRP3 expression in parenchymal cells of the kidney. The same applied to primary human podocytes in which NLRP3 agonists did not induce IL-1ß or IL-18 secretion. Diabetes induced identical glomerulomegaly in wildtype and Nphs2Cre;Nlrp3A350V mice but hyperfiltration-induced podocyte loss was attenuated and podocytes were larger in Nphs2Cre;Nlrp3A350V mice, an effect reversible with feeding the NLRP3 inflammasome antagonist ß-hydroxy-butyrate. Ultrastructural analysis of the slit diaphragm was genotype-independent hence albuminuria was identical. Conclusion: Podocytes express low amounts of the NLRP3 inflammasome, if at all, and do not produce IL-1ß and IL-18, not even upon introduction of the A350V Muckle-Wells NLRP3 variant and upon induction of podocyte stress. NLRP3-mediated glomerular inflammation is limited to immune cells.
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Síndromes Periódicas Associadas à Criopirina , Diabetes Mellitus Experimental , Proteína 3 que Contém Domínio de Pirina da Família NLR , Podócitos , Animais , Humanos , Camundongos , Butiratos , Células Epiteliais , Inflamassomos , Interleucina-18 , Rim , Proteína 3 que Contém Domínio de Pirina da Família NLR/genéticaRESUMO
BACKGROUND: The objective of this study was to investigate the DRD2 rs1800497, rs1799732, rs1801028, DRD3 rs6280, and HTR2A rs6314, rs7997012, and rs6311 single-nucleotide polymorphism (SNP) correlations with resistance to second-generation antipsychotics (SGAs) in a real-world sample of patients with treatment-resistant mental disorders. METHODS: We divided 129 participants into a high treatment resistance (HTR) group (current treatment with two SGAs, or clozapine, or classic neuroleptics for a failure of previous SGAs trials) and a low treatment resistance (LTR) group (current treatment with one atypical antipsychotic). We used Next-Generation Sequencing on DNA isolated from peripheral blood samples to analyze the polymorphisms. We performed logistic regression to search for predictors of HTR membership. RESULTS: A diagnosis of schizophrenia significantly predicted the HTR membership compared to other diagnoses. Other predictors were the DRD3 rs6280 C|T (OR = 22.195) and T|T (OR = 18.47) vs. C|C, HTR2A rs7997012 A|G vs. A|A (OR = 6.859) and vs. G|G (OR = 2.879), and DRD2 rs1799732 I|I vs. D|I (OR = 12.079) genotypes. CONCLUSIONS: A diagnosis of schizophrenia and the DRD2 rs1799732, DRD3 rs6280, and HTR2A rs7997012 genotypes can predict high treatment resistance to SGAs.
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Acute kidney injury (AKI) is frequent, often fatal and, for lack of specific therapies, can leave survivors with chronic kidney disease (CKD). We characterize the distribution of tubular cells (TC) undergoing polyploidy along AKI by DNA content analysis and single cell RNA-sequencing. Furthermore, we study the functional roles of polyploidization using transgenic models and drug interventions. We identify YAP1-driven TC polyploidization outside the site of injury as a rapid way to sustain residual kidney function early during AKI. This survival mechanism comes at the cost of senescence of polyploid TC promoting interstitial fibrosis and CKD in AKI survivors. However, targeting TC polyploidization after the early AKI phase can prevent AKI-CKD transition without influencing AKI lethality. Senolytic treatment prevents CKD by blocking repeated TC polyploidization cycles. These results revise the current pathophysiological concept of how the kidney responds to acute injury and identify a novel druggable target to improve prognosis in AKI survivors.
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Injúria Renal Aguda , Insuficiência Renal Crônica , Injúria Renal Aguda/metabolismo , DNA/metabolismo , Progressão da Doença , Humanos , Rim/metabolismo , Poliploidia , RNA/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , SenoterapiaRESUMO
Crescentic glomerulonephritis is characterized by vascular necrosis and parietal epithelial cell hyperplasia in the space surrounding the glomerulus, resulting in the formation of crescents. Little is known about the molecular mechanisms driving this process. Inducing crescentic glomerulonephritis in two Pax2Cre reporter mouse models revealed that crescents derive from clonal expansion of single immature parietal epithelial cells. Preemptive and delayed histone deacetylase inhibition with panobinostat, a drug used to treat hematopoietic stem cell disorders, attenuated crescentic glomerulonephritis with recovery of kidney function in the two mouse models. Three-dimensional confocal microscopy and stimulated emission depletion superresolution imaging of mouse glomeruli showed that, in addition to exerting an anti-inflammatory and immunosuppressive effect, panobinostat induced differentiation of an immature hyperplastic parietal epithelial cell subset into podocytes, thereby restoring the glomerular filtration barrier. Single-cell RNA sequencing of human renal progenitor cells in vitro identified an immature stratifin-positive cell subset and revealed that expansion of this stratifin-expressing progenitor cell subset was associated with a poor outcome in human crescentic glomerulonephritis. Treatment of human parietal epithelial cells in vitro with panobinostat attenuated stratifin expression in renal progenitor cells, reduced their proliferation, and promoted their differentiation into podocytes. These results offer mechanistic insights into the formation of glomerular crescents and demonstrate that selective targeting of renal progenitor cells can attenuate crescent formation and the deterioration of kidney function in crescentic glomerulonephritis in mice.
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Glomerulonefrite , Podócitos , Animais , Modelos Animais de Doenças , Glomerulonefrite/tratamento farmacológico , Humanos , Rim/metabolismo , Camundongos , Panobinostat/uso terapêutico , Podócitos/metabolismo , Células-Tronco/metabolismoRESUMO
Sex and gender disparities have been reported for different types of non-reproductive cancers. Males are two times more likely to develop kidney cancer than females and have a higher death rate. These differences can be explained by looking at genetics and genomics, as well as other risk factors such as hypertension and obesity, lifestyle, and female sex hormones. Examination of the hormonal signaling pathways bring further insights into sex-related differences. Sex and gender-based disparities can be observed at the diagnostic, histological and treatment levels, leading to significant outcome difference. This review summarizes the current knowledge about sex and gender-related differences in the clinical presentation of patients with kidney cancer and the possible biological mechanisms that could explain these observations. Underlying sex-based differences may contribute to the development of sex-specific prognostic and diagnostic tools and the improvement of personalized therapies.
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Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.