Elena Lazzeri
@unifi.it
Department of Clinical and Experimental Biomedical Sciences
University of Florence
RESEARCH INTERESTS
Nephrology, stem cell biology
Scopus Publications
Scopus Publications
Lorenzo Salvati, Boaz Palterer, Elena Lazzeri, Emanuele Vivarelli, Marina Amendola, Marco Allinovi, Leonardo Caroti, Alessio Mazzoni, Laura Lasagni, Giacomo Emmi,et al.
Elsevier BV
Letizia De Chiara, Elena Lazzeri, and Paola Romagnani
Elsevier BV
Letizia De Chiara, Roberto Semeraro, Benedetta Mazzinghi, Samuela Landini, Alice Molli, Giulia Antonelli, Maria Lucia Angelotti, Maria Elena Melica, Laura Maggi, Carolina Conte,et al.
American Physiological Society
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.
Maria Melica, Maria Angelotti, Giulia Antonelli, Anna Peired, Carolina Conte, Letizia Chiara, Benedetta Mazzinghi, Elena Lazzeri, Laura Lasagni, and Paola Romagnani
Bio-Protocol, LLC
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.
Francesca Becherucci, Samuela Landini, Viviana Palazzo, Luigi Cirillo, Valentina Raglianti, Gianmarco Lugli, Lucia Tiberi, Elia Dirupo, Stefania Bellelli, Tommaso Mazzierli,et al.
Ovid Technologies (Wolters Kluwer Health)
Significance Statement To optimize the diagnosis of genetic kidney disorders in a cost-effective manner, we developed a workflow based on referral criteria for in-person evaluation at a tertiary center, whole-exome sequencing, reverse phenotyping, and multidisciplinary board analysis. This workflow reached a diagnostic rate of 67%, with 48% confirming and 19% modifying the suspected clinical diagnosis. We obtained a genetic diagnosis in 64% of children and 70% of adults. A modeled cost analysis demonstrated that early genetic testing saves 20% of costs per patient. Real cost analysis on a representative sample of 66 patients demonstrated an actual cost reduction of 41%. This workflow demonstrates feasibility, performance, and economic effect for the diagnosis of genetic kidney diseases in a real-world setting. Background Whole-exome sequencing (WES) increases the diagnostic rate of genetic kidney disorders, but accessibility, interpretation of results, and costs limit use in daily practice. Methods Univariable analysis of a historical cohort of 392 patients who underwent WES for kidney diseases showed that resistance to treatments, familial history of kidney disease, extrarenal involvement, congenital abnormalities of the kidney and urinary tract and CKD stage ≥G2, two or more cysts per kidney on ultrasound, persistent hyperechoic kidneys or nephrocalcinosis on ultrasound, and persistent metabolic abnormalities were most predictive for genetic diagnosis. We prospectively applied these criteria to select patients in a network of nephrology centers, followed by centralized genetic diagnosis by WES, reverse phenotyping, and multidisciplinary board discussion. Results We applied this multistep workflow to 476 patients with eight clinical categories (podocytopathies, collagenopathies, CKD of unknown origin, tubulopathies, ciliopathies, congenital anomalies of the kidney and urinary tract, syndromic CKD, metabolic kidney disorders), obtaining genetic diagnosis for 319 of 476 patients (67.0%) (95% in 21 patients with disease onset during the fetal period or at birth, 64% in 298 pediatric patients, and 70% in 156 adult patients). The suspected clinical diagnosis was confirmed in 48% of the 476 patients and modified in 19%. A modeled cost analysis showed that application of this workflow saved 20% of costs per patient when performed at the beginning of the diagnostic process. Real cost analysis of 66 patients randomly selected from all categories showed actual cost reduction of 41%. Conclusions A diagnostic workflow for genetic kidney diseases that includes WES is cost-saving, especially if implemented early, and is feasible in a real-world setting.
Letizia De Chiara, Carolina Conte, Roberto Semeraro, Paula Diaz-Bulnes, Maria Lucia Angelotti, Benedetta Mazzinghi, Alice Molli, Giulia Antonelli, Samuela Landini, Maria Elena Melica,et al.
Springer Science and Business Media LLC
AbstractAcute 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.
Maria Elena Melica, Giulia Antonelli, Roberto Semeraro, Maria Lucia Angelotti, Gianmarco Lugli, Samuela Landini, Fiammetta Ravaglia, Gilda La Regina, Carolina Conte, Letizia De Chiara,et al.
American Association for the Advancement of Science (AAAS)
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.
Letizia De Chiara, Elena Lazzeri, and Paola Romagnani
Oxford University Press (OUP)
Letizia De Chiara, Elena Lazzeri, Maria Lucia Angelotti, Carolina Conte, Anna Julie Peired, Giulia Antonelli, Maria Elena Melica, Benedetta Mazzinghi, Laura Lasagni, and Paola Romagnani
Oxford University Press (OUP)
Letizia De Chiara, Gianmarco Lugli, Gianluca Villa, Valentina Raglianti, Faeq Husain-Syed, Fiammetta Ravaglia, Paola Romagnani, and Elena Lazzeri
MDPI AG
Acute kidney injury (AKI) is a life-threatening condition characterized by a rapid and transient decrease in kidney function. AKI is part of an array of conditions collectively defined as acute kidney diseases (AKD). In AKD, persistent kidney damage and dysfunction lead to chronic kidney disease (CKD) over time. A variety of insults can trigger AKI; however, chemotherapy-associated nephrotoxicity is increasingly recognized as a significant side effect of chemotherapy. New biomarkers are urgently needed to identify patients at high risk of developing chemotherapy-associated nephrotoxicity and subsequent AKI. However, a lack of understanding of cellular mechanisms that trigger chemotherapy-related nephrotoxicity has hindered the identification of effective biomarkers to date. In this review, we aim to (1) describe the known and potential mechanisms related to chemotherapy-induced AKI; (2) summarize the available biomarkers for early AKI detection, and (3) raise awareness of chemotherapy-induced AKI.
Giulia Cantini, Laura Fei, Letizia Canu, Elena Lazzeri, Mariangela Sottili, Michela Francalanci, Maria Lucia Angelotti, Giuseppina De Filpo, Tonino Ercolino, Stefania Gelmini,et al.
MDPI AG
Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis when metastatic and scarce treatment options in the advanced stages. In solid tumors, the chemokine CXCL12/CXCR4 axis is involved in the metastatic process. We demonstrated that the human adrenocortex expressed CXCL12 and its cognate receptors CXCR4 and CXCR7, not only in physiological conditions, but also in ACC, where the receptors’ expression was higher and the CXCL12 expression was lower than in the physiological conditions. In a small pilot cohort of 22 ACC patients, CXCL12 negatively correlated with tumor size, stage, Weiss score, necrosis, and mitotic activity. In a Kaplan–Meier analysis, the CXCL12 tumor expression significantly predicted disease-free, progression-free, and overall survival. In vitro treatment of the primary ACC H295R and of the metastatic MUC-1 cell line with the PPARγ-ligand rosiglitazone (RGZ) dose-dependently reduced proliferation, resulting in a significant increase in CXCL12 and a decrease in its receptors in the H295R cells only, with no effect on the MUC-1 levels. In ACC mouse xenografts, tumor growth was inhibited by the RGZ treatment before tumor development (prevention-setting) and once the tumor had grown (therapeutic-setting), similarly to mitotane (MTT). This inhibition was associated with a significant suppression of the tumor CXCR4/CXCR7 and the stimulation of human CXCL12 expression. Tumor growth correlated inversely with CXCL12 and positively with CXCR4 expression, suggesting that local CXCL12 may impair the primary tumor cell response to the ligand gradient that may contribute to driving the tumor progression. These findings indicate that CXCL12/CXCR4 may constitute a potential target for anti-cancer agents such as rosiglitazone in the treatment of ACC.
Letizia De Chiara, Carolina Conte, Giulia Antonelli, and Elena Lazzeri
MDPI AG
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.
Anna Julie Peired, Riccardo Campi, Maria Lucia Angelotti, Giulia Antonelli, Carolina Conte, Elena Lazzeri, Francesca Becherucci, Linda Calistri, Sergio Serni, and Paola Romagnani
MDPI AG
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.
Anna Julie Peired, Elena Lazzeri, Francesco Guzzi, Hans-Joachim Anders, and Paola Romagnani
Elsevier BV
Epidemiological studies document strong associations between acute or chronic kidney injury and kidney tumors. However, whether these associations are linked by causation, and in which direction, is unclear. Accumulating data from basic and clinical research now shed light on this issue and prompt us to propose a new pathophysiological concept with immanent implications in the management of patients with kidney disease and patients with kidney tumors. As a central paradigm, this review proposes the mechanisms of kidney damage and repair that are active during acute kidney injury but also during persistent injuries in chronic kidney disease as triggers of DNA damage promoting the expansion of (pre-)malignant cell clones. As renal progenitors have been identified by different studies as the cell of origin for several benign and malignant kidney tumors, we discuss how the different types of kidney tumors relate to renal progenitors at specific sites of injury and to germline or somatic mutations in distinct signaling pathways. We explain how known risk factors for kidney cancer rather represent risk factors for kidney injury as an upstream cause of cancer. Finally, we propose a new role for nephrologists in kidney cancer, i.e. the primary and secondary prevention and treatment of kidney injury to reduce incidence, prevalence, and recurrence of kidney cancer.
Anna Julie Peired, Benedetta Mazzinghi, Letizia De Chiara, Francesco Guzzi, Laura Lasagni, Paola Romagnani, and Elena Lazzeri
Informa UK Limited
Anna Julie Peired, Giulia Antonelli, Maria Lucia Angelotti, Marco Allinovi, Francesco Guzzi, Alessandro Sisti, Roberto Semeraro, Carolina Conte, Benedetta Mazzinghi, Sara Nardi,et al.
American Association for the Advancement of Science (AAAS)
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.
Francesco Guzzi, Luigi Cirillo, Rosa Maria Roperto, Paola Romagnani, and Elena Lazzeri
MDPI AG
Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, behind the ability of a single, acute, apparently self-limiting event to drive chronic kidney disease progression are yet to be explained. This acute injury could promote progression to chronic disease through different pathways involving the endothelium, the inflammatory response and the development of fibrosis. The interplay among endothelial cells, macrophages and other immune cells, pericytes and fibroblasts often converge in the tubular epithelial cells that play a central role. Recent evidence has strengthened this concept by demonstrating that injured tubules respond to acute tubular necrosis through two main mechanisms: The polyploidization of tubular cells and the proliferation of a small population of self-renewing renal progenitors. This alternative pathophysiological interpretation could better characterize functional recovery after AKI.
Elena Lazzeri, Maria Lucia Angelotti, Carolina Conte, Hans-Joachim Anders, and Paola Romagnani
Elsevier BV
Maria Lucia Angelotti, Elena Lazzeri, and Paola Romagnani
Elsevier
Elena Lazzeri, Maria Lucia Angelotti, Anna Peired, Carolina Conte, Julian A. Marschner, Laura Maggi, Benedetta Mazzinghi, Duccio Lombardi, Maria Elena Melica, Sara Nardi,et al.
Springer Science and Business Media LLC
Anna Manonelles, Roser Guiteras, Edoardo Melilli, Elena Lazzeri, Montse Goma, Elena Crespo, Oriol Bestard, Anna Sola, Paola Romagnani, and Josep M. Cruzado
Frontiers Media SA
Benedetta Mazzinghi, Paola Romagnani, and Elena Lazzeri
Informa UK Limited
Paola Romagnani, Sabrina Giglio, Maria Lucia Angelotti, Aldesia Provenzano, Francesca Becherucci, Benedetta Mazzinghi, Susanna Müller, Kerstin Amann, Marc Weidenbusch, Simone Romoli,et al.
Oxford University Press (OUP)
Elena Lazzeri, Paola Romagnani, and Laura Lasagni
Informa Healthcare