Sexually Dimorphic Gene Expression in Rat Proximal Tubules Suggests Activation of the Intrarenal Renin Angiotensin System and Elevated Transport Rates in Males
Authors: Kim Najeong , Kramer Benjamin , Gonzalez-Vicente Agustin 
Published: May 2024

Introduction: Sexual dimorphism affects various organ systems, including renal and cardiovascular. The renin-angiotensin system (RAS) plays a pivotal role in regulating fluid homeostasis and blood pressure, with males being generally more sensitive to the hypertensive actions of angiotensin II (AngII). Proximal tubules (PT)s reabsorb 60-70% of filtered water, sodium, and bicarbonate and present sexually dimorphic biology. In addition, PTs are a key element of the intrarenal RAS and the production site of angiotensinogen ( Agt, AGT) and derived bioactive peptides. These peptides exert autocrine, as well as paracrine effects in distal portions of the nephron, regulating salt and water reabsorption. Hypothesis: We hypothesize that the increased sensitivity to the hypertensive actions of AngII in males is due to activation of the intrarenal RAS. Methods: We used 3 male and 3 female pools of whole kidney single-cell RNAseq transcriptomes to study gene expression differences across sexes in different segments of the nephron. Results: We identified sex-differentially expressed genes (DEGs) in all segments of the nephron, with the majority of DEG mapping to the PT. Analyzing all three PT segments together, we found 86 upregulated genes in females and 104 in males. Pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) highlighted pathways associated with glutathione biosynthesis and metabolism in females, while males presented greater expression of genes associated with the tricarboxylic acid cycle and mineral absorption, including the γ-subunit of the Na,K-ATPase ( Fxyd2). Differential expression of genes on each sub-segment of the PTs, namely S1, S2, and S3, showed the following number of upregulated genes: Females: 39, 37, and 73 in S1, S2, and S3, respectively; and Males: 67, 57, and 105 in S1, S2, and S3, respectively. This data indicates that S3 exhibits the largest sexually dimorphic transcriptomes. Pathway enrichment on S3 DEG in both males and females showed similar enrichment terms as in whole PTs. However, at this resolution, males also present upregulation of RAS genes, including Agt, and two proteases involved in the metabolism of angiotensin peptides: aminopeptidase A ( Enpep, APA) and prolyl endopeptidase ( Prep, PEP). APA and PEP can both cleave AngII to bioactive peptides AngIII and Ang(1-7), respectively. Conclusion: We conclude that the intrarenal RAS is upregulated in male PT.S3. The increase in AGT and proteases capable of metabolizing AngII suggest that this peptide may be elevated. Analyzing the expression of RAS genes alone does not allow us to infer a resultant effect on Na handling, as AngII, AngIII, and Ang(1-7) could exert both natriuretic and anti-natriuretic effects. However, enrichment terms associated with mineral transport and energy demands suggest active mineral transport prevails in males. Funding sources: This work was supported in part by CWRU BGT670107 and NIH-NIDDK DK128304 grants to AGV. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.