AUTHOR=Liu Wen-Bin , Fermin Damian , Xu An-Long , Kopp Jeffrey B. , Xu Qihe 

TITLE=Single-cell RNA sequencing data locate ALDH1A2-mediated retinoic acid synthetic pathway to glomerular parietal epithelial cells

JOURNAL=Experimental Biology and Medicine

VOLUME=249

YEAR=2024

URL=https://www.ebm-journal.org/journals/experimental-biology-and-medicine/articles/10.3389/ebm.2024.10167

DOI=10.3389/ebm.2024.10167

ISSN=1535-3699

ABSTRACT=<p>Aldehyde dehydrogenase 1, family member A2, is a retinoic acid-synthesizing enzyme encoded by <italic>Aldh1a2</italic> in mice and <italic>ALDH1A2</italic> in humans. This enzyme is indispensable for kidney development, but its role in kidney physiology and pathophysiology remains to be fully defined. In this review, we mined single-cell and single-nucleus RNA sequencing databases of mouse and human kidneys and found that glomerular parietal epithelial cells (PECs) express a full set of genes encoding proteins needed for cellular vitamin A uptake, intracellular transport, and metabolism into retinoic acid. In particular, <italic>Aldh1a2/ALDH1A2</italic> mRNAs are selectively enriched in mouse and human PECs. <italic>Aldh1a2</italic> expression in PECs is greatly increased in a mouse model of anti-glomerular basement membrane glomerulonephritis and moderately induced in a mouse model of ischemia-reperfusion acute kidney injury. <italic>Aldh1a2</italic> expression in PECs is substantially repressed in a chronic kidney disease mouse model combining diabetes, hypertension, and partial nephrectomy and is moderately repressed in mouse models of focal segmental glomerulosclerosis and diabetic nephropathy. Single-nucleus RNA sequencing data show that <italic>ALDH1A2</italic> mRNA expression in PECs is diminished in patients with chronic kidney disease associated with diabetes, hypertension and polycystic kidney disease. In addition to data mining, we also performed Spearman’s rank correlation coefficient analyses and identified gene transcripts correlated with <italic>Aldh1a2/ALDH1A2</italic> transcripts in mouse PECs and PEC subtypes, and in human PECs of healthy subjects and patients with AKI or CKD. Furthermore, we conducted Gene Ontology pathway analyses and identified the biological pathways enriched among these <italic>Aldh1a2/ALDH1A2</italic>-correlated genes. Our data mining and analyses led us to hypothesize that ALDH1A2<italic>-</italic>mediated retinoic acid synthesis in PECs plays a yet-undefined role in the kidney and that its dysregulation mediates injury. Conditional, PEC-selective <italic>Aldh1a2</italic> knockout, RNA silencing and transgenic mouse models will be useful tools to test this hypothesis. Clinical studies on genetics, epigenetics, expression and functions of <italic>ALDH1A2</italic> and other genes needed for retinoic acid biosynthesis and signaling are also warranted.</p>