ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: TH-PO069

AKI Drives Papillary Renal Cell Carcinoma Formation from Tubular Progenitor Cells

Session Information

Category: Acute Kidney Injury

  • 101 AKI: Epidemiology, Risk Factors, and Prevention

Authors

  • Peired, Anna Julie, University of Florence, Florence, Italy
  • Antonelli, Giulia, University of Florence, Florence, Italy
  • Angelotti, Maria Lucia, University of Florence, Florence, Italy
  • Sisti, Alessandro, University of Florence, Florence, Italy
  • Allinovi, Marco, University of Florence, Florence, Italy
  • Romagnani, Paola, University of Florence, Florence, Italy
Background

Renal cell carcinoma (RCC) accounts for 2% of all cancers, with about 190,000 new cases per year worldwide. As the Notch pathway has a critical role in kidney injury and repair, and Notch hyperexpression was reported in patients with RCC, we hypothesized that a persistent activation of the Notch pathway may drive tubular epithelial cell (TEC) hyperplasia, leading to cancer formation.
Other risk factors for RCC include obesity, diabetes, hypertension and genetic factors, but the majority of cancers occur in apparent absence of clear risk factors. As tissue injury is an important cofactor for many types of cancers, we proposed to verify whether acute kidney injury (AKI) plays a role in RCC development.

Methods

We developed mouse models in which the intracellular domain of Notch 1 (NICD1) is expressed constitutively by all Pax8+ TECs (Pax8/NICD1) or only by Pax2+ renal progenitors (Pax2/NICD1) upon induction in adult mice. Both models were further bred with Confetti mice, allowing clonal analysis of the lesions.
Following induction, the mice were either left to age for 9 months or underwent unilateral ischemia-reperfusion injury (IRI), an experimental model of AKI, and were sacrificed at 28 days.

Results

At 9 months, Pax8/NICD1 mice presented a significant decline of renal excretory function as well as numerous, multicentric and progressive pretumoral and tumoral lesions. Histological analysis indicate the presence of papillary RCCs (pRCCs). In Pax8/NICD1/Confetti mice, we observed that most of the pRCCs were mono- or biclonal, suggesting that they could originate from a local stem cell/progenitor population.
Pax2/NICD1 mice presented exclusively papillary tumors. Lineage tracing in Pax2/NICD1/Confetti mice identified single Pax2+ tubular progenitors as the source of pRCCs.
Mice subjected to IRI presented mono- and biclonal papillary tumors in only 28 days, indicating that AKI strongly accelerated the development of pRCCs.

Conclusion

These mouse models represent useful new tools to study the mechanisms of tumor development in the kidney and indicate Pax2+ renal progenitors as the cell of origin of pRCC. Additionally, this study provides the first experimental demonstration of the link between AKI and the development of papillary tumors, with important clinical implications for RCC patients.

Funding

  • Private Foundation Support