Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells

2020 ◽  
Vol 12 (536) ◽  
pp. eaaw6003 ◽  
Author(s):  
Anna Julie Peired ◽  
Giulia Antonelli ◽  
Maria Lucia Angelotti ◽  
Marco Allinovi ◽  
Francesco Guzzi ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Progenitor Cells ◽  
Renal Cell ◽  
Tissue Injury ◽  
Kidney Injury ◽  
Lineage Tracing ◽  
Cell Of Origin ◽  
Renal Progenitor Cells ◽  
Renal Progenitor

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.

scholarly journals SaO032PAPILLARY RENAL CELL CARCINOMA ORIGINATES FROM A POPULATION OF RENAL PROGENITOR CELLS AND IS PROMOTED BY ACUTE KIDNEY INJURY

2018 ◽  
Vol 33 (suppl_1) ◽  
pp. i328-i328
Author(s):  
Anna Peired ◽  
Giulia Antonelli ◽  
Maria Lucia Angelotti ◽  
Alessandro Sisti ◽  
Marco Allinovi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Acute Kidney Injury ◽  
Cell Carcinoma ◽  
Progenitor Cells ◽  
Renal Cell ◽  
Kidney Injury ◽  
Renal Progenitor Cells ◽  
Renal Progenitor

scholarly journals WNT/β-Catenin Signaling Is Required for Integration of CD24+Renal Progenitor Cells into Glycerol-Damaged Adult Renal Tubules

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Zhao Zhang ◽  
Diana M. Iglesias ◽  
Rachel Corsini ◽  
LeeLee Chu ◽  
Paul Goodyer
Keyword(s):  
Progenitor Cells ◽  
Kidney Injury ◽  
Perinatal Period ◽  
Renal Tubules ◽  
Adult Mice ◽  
Renal Progenitor Cells ◽  
Nephron Progenitor ◽  
Canonical Wnt ◽  
Renal Progenitor

During development, nephron progenitor cells (NPC) are induced to differentiate by WNT9b signals from the ureteric bud. Although nephrogenesis ends in the perinatal period, acute kidney injury (AKI) elicits repopulation of damaged nephrons. Interestingly, embryonic NPC infused into adult mice with AKI are incorporated into regenerating tubules. Since WNT/β-catenin signaling is crucial for primary nephrogenesis, we reasoned that it might also be needed for the endogenous repair mechanism and for integration of exogenous NPC. When we examined glycerol-induced AKI in adult mice bearing aβ-catenin/TCF reporter transgene, endogenous tubular cells reexpressed the NPC marker, CD24, and showed widespreadβ-catenin/TCF signaling. We isolated CD24+cells from E15 kidneys of mice with the canonical WNT signaling reporter. 40% of cells responded to WNT3ain vitroand when infused into glycerol-injured adult, the cells exhibitedβ-catenin/TCF reporter activity when integrated into damaged tubules. When embryonic CD24+cells were treated with aβ-catenin/TCF pathway inhibitor (IWR-1) prior to infusion into glycerol-injured mice, tubular integration of cells was sharply reduced. Thus, the endogenous canonicalβ-catenin/TCF pathway is reactivated during recovery from AKI and is required for integration of exogenous embryonic renal progenitor cells into damaged tubules. These events appear to recapitulate the WNT-dependent inductive process which drives primary nephrogenesis.

MO060ACUTE KIDNEY INJURY PROMOTES DEVELOPMENT OF A PAPILLARY RENAL CELL ADENOMA-CARCINOMA SEQUENCE FROM RENAL PROGENITORS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Anna Julie Peired ◽  
Marco Allinovi ◽  
Giulia Antonelli ◽  
Maria Lucia Angelotti ◽  
Francesco Guzzi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Single Cell ◽  
Renal Cell ◽  
Tissue Injury ◽  
Lineage Tracing ◽  
Molecular Signature ◽  
Research Network ◽  
Wild Type ◽  
Renal Progenitors

Abstract Background and Aims Renal cell carcinoma (RCC) accounts for 2% of all cancers, with about 190,000 new cases per year worldwide. Risk factors for RCC include obesity, diabetes, hypertension and genetic factors, but the majority of cancers occur in apparent absence of clear risk factors. Acute tissue injury (AKI) causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. We proposed to verify whether AKI plays a role in RCC development, and to identify the cellular origin of RCC. Method We used the following techniques: 1. observational, retrospective clinical trial to identify a possible association of AKI with RCC. 2. Experimental AKI induction in wild-type mice to study tumor development over 36 weeks. 3. Analysis of TCGA Research Network dataset on human papillary RCC (pRCC) molecular characterization, focusing on AKI-driven pathways. 4. Development of mouse models in which the intracellular domain of Notch 1 (NICD1), a molecule modulated during AKI, is expressed constitutively by all Pax8+ tubular epithelial cells (Pax8/NICD1) or only by Pax2+ renal progenitors (Pax2/NICD1) upon induction in adult mice. The mice were sacrificed at 36 weeks or 4 weeks after AKI. 5. Clonal analysis of tumoral lesions with Confetti reporter. 6. Examination of single cell RNA sequencing (RNAseq) data from pRCC patients. Results We observed that an AKI episode is a major risk factor for pRCC development and recurrence in patients. Wild-type mice subjected to AKI developed pRCC over time in an adenoma-carcinoma sequence, corroborating our human findings. Among AKI-related pathways, Notch1 overexpression in human pRCC associated with worse outcome, prompting us to generate Notch1-overexpressing mice. At 36 weeks o at 4 weeks following AKI, Pax8/NICD1 mice presented a significant decline of renal excretory function as well as type 2 pRCCs. Confetti lineage tracing showed that most of the pRCCs were monoclonal or biclonal, suggesting that they could originate from a local stem cell/progenitor population. Pax2/NICD1 mice presented type 2 pRCCs, and lineage tracing identified single Pax2+ tubular progenitors as the source of pRCCs. Single cell RNAseq analysis confirmed that the molecular signature of the pRCC cell of origin matched the one of human tubular progenitors. Conclusion This study expose the link between AKI and pRCC development in patients, with important clinical implications. In mice, AKI promotes long-term development of type 2 papillary tumors by activating the AKI-associated Notch1 pathway. Additionally, pRCC originates from clonal proliferation of renal progenitors in a classical adenoma-carcinoma sequence leading to invasive pRCC growth and metastatization in mice.

scholarly journals A Porthole over AKI: Cell Dynamics in Damage and Repair

Nephron ◽  
2020 ◽  
Vol 144 (12) ◽  
pp. 650-654
Author(s):  
Luca Bordoni ◽  
Donato Sardella ◽  
Ina Maria Schiessl
Keyword(s):  
Acute Kidney Injury ◽  
Renal Cell ◽  
Kidney Injury ◽  
Cell Types ◽  
Cell Interactions ◽  
Intravital Imaging ◽  
Cell Dynamics ◽  
Powerful Technique ◽  
Increased Risk ◽  
Cell Crosstalk

Acute kidney injury (AKI) is associated with an increased risk of CKD. Injury-induced multifaceted renal cell-to-cell crosstalk can either lead to successful self-repair or chronic fibrosis and inflammation. In this mini-review, we will discuss critical renal cell types acting as victims or executioners in AKI pathology and introduce intravital imaging as a powerful technique to further dissect these cell-to-cell interactions.

scholarly journals miR-34b-5p promotes renal cell inflammation and apoptosis by inhibiting aquaporin-2 in sepsis-induced acute kidney injury

Renal Failure ◽  
2021 ◽  
Vol 43 (1) ◽  
pp. 291-301
Author(s):  
Caifa Zheng ◽  
Dansen Wu ◽  
Songjing Shi ◽  
Liming Wang
Keyword(s):  
Acute Kidney Injury ◽  
Renal Cell ◽  
Kidney Injury ◽  
Aquaporin 2
Sign in / Sign up

Export Citation Format

Share Document