Abstract: FR-PO702
Proteinuria Induces Tubular Cell Proliferation in Nephrotic Syndrome Model Mice Without Causing Tubular Injury
Session Information
- Glomerular Diseases: From Inflammation to Fibrosis - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: From Inflammation to Fibrosis
Authors
- Suzuki, Yuya, Niigata Daigaku, Niigata, Niigata, Japan
- Kaseda, Ryohei, Niigata Daigaku, Niigata, Niigata, Japan
- Nakagawa, Yusuke, Niigata Daigaku, Niigata, Niigata, Japan
- Narita, Ichiei, Niigata Daigaku, Niigata, Niigata, Japan
Background
Proteinuria exhibits a robust association with the progression of kidney diseases and causes pathological effects on tubular cells. Nevertheless, the precise molecular mechanisms underlying tubular injury induced by proteinuria remain largely unknown. To elucidate the transcriptome alterations in the kidney resulting from proteinuria, we conducted an RNA sequencing (RNA-seq) analysis on a mouse model of nephrotic syndrome.
Methods
We used NEP25 mice, which express the human CD25 receptor on podocytes. Proteinuria was induced in these mice through the administration of an immunotoxin targeting the human CD25 receptor, LMB2 (0.625 ng/g body weight). After a period of seven days following LMB2 injection, the mice were euthanized, and RNA was extracted from the whole kidney. RNA-seq was performed using Illumina NovaSeq, and differential expression genes (DEGs) were identified using the DESeq2 package in R. Subsequently, we conducted multiple immunostaining and in situ hybridization (ISH) of the DEGs to determine their cellular localization and specific cell types.
Results
Following the administration of LMB2, Nep25 mice exhibited significant proteinuria without exhibiting kidney disfunction or histological damage. Through our kidney RNA-seq analysis of Nep25 mice, we identified 562 up-regulated and 430 down-regulated genes. Enrichment analysis revealed a notable up-regulation of genes associated with cell proliferation, such as Mki67. Notably, we observed a significant up-regulation of the transcription factor Foxm1, known to be involved in cell proliferation. Immunostaining and ISH confirmed the co-expression of Ki67 and Foxm1 in various tubular cells, including the proximal tubule, loop of Henle, distal tubule, and collecting duct.
Conclusion
The RNA-seq analysis of nephrotic syndrome model mice revealed that tubular cell proliferation was triggered by extensive proteinuria without causing kidney dysfunction or histological damage. The up-regulated genes, including Foxm1, have been previously associated not only with cell proliferation but also with tissue fibrosis. Consequently, the modulation of these gene functions is possible to serve as novel targets for chronic kidney disease treatment.