Nephrotic syndrome induces the upregulation of cell proliferation-related genes in tubular cells in mice.

Abstract

Massive proteinuria, dyslipidemia, and hypoalbuminemia induced by nephrotic syndrome (NS) secondarily affect tubular cells. We conducted an RNA sequencing (RNA-seq) analysis using a mouse model of focal segmental glomerulosclerosis to clarify the impact of NS on tubular cells. We used transgenic mice expressing hCD25 in podocytes (Nep25) to induce NS by injecting human CD25-specific immunotoxin (LMB2) at a dose of 0.625ng/g body weight. Seven days after LMB2 injection, we extracted RNA from the whole kidney and conducted an RNA-seq analysis. Subsequently, we conducted multiple immunostaining and in situ hybridization (ISH) of differentially expressed genes (DEGs) to identify their locations and associated cell types. We also investigated the expression levels of DEGs in an additional mouse model of NS induced by adriamycin. After NS induction, 562 upregulated and 430 downregulated DEGs were identified using RNA-seq. An enrichment analysis revealed the upregulation of cell proliferation-related genes. We observed significant upregulation of Foxm1, a transcription factor linked to cell proliferation. Immunostaining and ISH showed that various tubular cells expressed Mki67 and Foxm1 during NS development. The adriamycin-induced NS model also demonstrated the upregulation of Mki67 and Foxm1 in tubular cells. NS induced the upregulation of cell proliferation-related genes in tubular cells without detectable renal dysfunction. Our findings may contribute to understanding the pathological effects of nephrotic syndrome on tubular cells.