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Kidney Week

Abstract: TH-PO742

Identification of Intercellular Communication Involved in the Progression of Tubulointerstitial Fibrosis Common to Podocyte Injury and Ischemia-Reperfusion Injury Models

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Imai, Atsuhiro, Osaka Daigaku Daigakuin Igakukei Kenkyuka Igakubu Igaku Senko, Suita, Osaka, Japan
  • Matsui, Isao, Osaka Daigaku Daigakuin Igakukei Kenkyuka Igakubu Igaku Senko, Suita, Osaka, Japan
  • Okushima, Hiroki, Osaka Daigaku Daigakuin Igakukei Kenkyuka Igakubu Igaku Senko, Suita, Osaka, Japan
  • Katsuma, Yusuke, Osaka Daigaku Daigakuin Igakukei Kenkyuka Igakubu Igaku Senko, Suita, Osaka, Japan
  • Matsumoto, Ayumi, Osaka Daigaku Daigakuin Igakukei Kenkyuka Igakubu Igaku Senko, Suita, Osaka, Japan
  • Minami, Satoshi, Osaka Daigaku Daigakuin Igakukei Kenkyuka Igakubu Igaku Senko, Suita, Osaka, Japan
  • Yamamoto, Takeshi, Osaka Daigaku Daigakuin Igakukei Kenkyuka Igakubu Igaku Senko, Suita, Osaka, Japan
  • Inoue, Kazunori, Osaka Daigaku Daigakuin Igakukei Kenkyuka Igakubu Igaku Senko, Suita, Osaka, Japan
  • Isaka, Yoshitaka, Osaka Daigaku Daigakuin Igakukei Kenkyuka Igakubu Igaku Senko, Suita, Osaka, Japan
Background

Tubulointerstitial fibrosis (TF) is the final common pathway of progressive chronic kidney disease. The fibrogenic niche, a specialized microenvironment that triggers the differentiation of myofibroblasts (MF), is one of the critical therapeutic targets for TF. However, it remains uncertain what kind of intercellular communication shapes the fibrogenic niche.

Methods

Podocyte-specific Tln1 knockout (Tln1 KO) in C57BL/6J background mice (Tln1 fl/fl Nphs2 rtTA TetO - Cre) and an ischemia-reperfusion injury (IRI) model on C57BL/6 wild-type mice were used as animal models for TF. Tln1WT/WT Nphs2 rtTA TetO - Cre mice and sham-operated mice served as the controls. Kidney samples were collected on day 10 and week 5 after initiation of doxycycline induction for Tln1 KO mice and on days 2, 5, and 14 for the IRI model. The kidney samples were subjected to several analyses, including single-cell RNA sequencing (scRNA-seq).

Results

Histological examinations and real-time PCR analyses confirmed the development of TF lesions at week 5 in Tln1 KO mice and at day 14 in the IRI model. scRNA-seq analyses of a combined dataset from the two animal models identified 21 cell clusters. As TF progressed, clusters of injured proximal tubules (Inj-PT), impaired Henle's loops, MFs, and inflammatory cells appeared in common in both animal models. CellChat analyses of the inter-cluster communication revealed the closest communication between the Inj-PT and MF clusters. The communication between these two clusters included Spp1-Itgb1/5 and Pdgfa/b-Pdgfrb, Mdk-Sdc1/2/4, and Bmp6-Acvr1 signaling. The Inj-PT cluster expressed high levels of Havcr1 that encodes kidney injury molecule 1.

Conclusion

These results indicated that Havcr1-positive proximal tubular cells communicate strongly with myofibroblasts in both animal models. Although further experiments are required, these intercellular communications may contribute to developing a fibrogenic niche.