The same cell types of different species express common genes for their conserved structure and function. They also express some different genes that are important for each of them, respectively. Identification of genes uniquely functioning in a cell type of human would provide insights into the pathophysiology of the cell type in disease. To identify genes uniquely essential for human glomerular podocytes in kidney, we compared the gene expression profiles of human and mouse podocytes based on scRNA-seq databases, and found 10 genes that are highly expressed in human but not mouse podocytes. We knocked down these genes in human podocyte cell line (HPC) using siRNA, and found that knockdown of these genes resulted in viability reduction, migration alteration, or dedifferentiation in the HPC cells, suggesting that these genes function to maintain the survival, structure and function of human podocytes in normal physiology. Among these genes, FBXO21 encodes an E3 ligase in the complex of SCFs (SKP1-cullin-F-box), and studies have shown that FBXO21 targets EID1 for ubiquitination and degradation. EID1 is a transcription regulator and expressed in human podocytes. Previously, EID1 was found to be induced in neurons of patients with Alzheimer's disease (AD), and transgenic overexpression of EID1 caused damages on neuronal cells, leading to AD-like phenotypes in mice. Interestingly, neuronal cells and podocytes are known to share many similarities in cellular structure and function, gene expression, and signaling pathways. Importantly, we found with the Nephroseq that FBXO1 is greatly downregulated in various glomerular diseases, we therefore speculate that EID1 protein is increased in podocytes in various glomerular diseases and facilitates podocyte injury by enhancing the expression of genes that are deleterious to podocytes. We are currently testing this hypothesis concerning the mechanism underlying FBXO21’s protective effect and would hopefully reveal a novel pathway mediated by FBXO21 that protects human but not mouse podocytes. FBXO21 is a potential therapeutic target for glomerular diseases.

Podocyte, Essential Gene, Ubiquitination, FBXO21, EID1