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Abstract: SA-PO966

Gut Microbiota Modulates Gene Expression in the Kidney

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Moore, Brittni, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Xu, Jiaojiao, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Pluznick, Jennifer L., Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

Group or Team Name

  • Pluznick Lab
Background

Gut microbes impact host gene expression in peripheral tissues; however, it is unknown whether gut microbes influence renal gene expression.

Methods

Germ-free (GF; lacking gut microbes) and conventionalized (Conv; GF mice given gut microbes by oral gavage at 4 wks of age) C57Bl/6J mice were compared by bulk RNA sequencing (RNA-Seq) of kidney, liver, and large intestine. At 8 wks of age, GF and Conv mice were sacrificed, tissues processed, and fecal pellets from Conv mice collected for 16S rRNA sequencing. Differentially expressed genes (DEGs) were defined as log2foldchange(log2fc)≥±0.5, p<0.05, and basemean≥15 TPM. For antibiotic-treated mice(ABX), conventional C57Bl/6 mice were given ampicillin (1g/L), neomycin (1g/L), and vancomycin (0.5g/L) in drinking water for 9 wks and kidneys were collected for real-time quantitative PCR (qPCR).

Results

Comparing Conv and GF mice (both sexes analyzed together, n=3-4/sex/condition) revealed 918 DEGs in kidney, 1701 in liver, and 1324 in large intestine. In males, 85% of kidney DEGs did not change in liver or large intestine. In females, 80% of DEGs were kidney-specific. 4 genes were changed in all 3 tissues in males (Per1, Foxo3, Mt1, Mt2), and 6 genes in females (Per2, Mt1, Mt2, Jchain, Extl1, Lpl). Mt1 and Mt2 were the only genes increased in GF mice in both sexes and in all 3 tissues. In kidney, Mt1 expression was upregulated by log2fc 1.10±0.22 (p<0.001) in GF vs Conv males (n=4,4), and by log2fc = 0.57±0.22 (p=0.01) in GF vs Conv females (n=4,4). Mt2 was also increased in GF males (log2fc = 1.44±0.29, p <0.001) and GF females (log2fc = 0.80±0.29, p= 0.006) vs Conv. To determine if changes in Mt1 and Mt2 are due to the absence of gut microbes, we performed qPCR using kidneys from ABX vs conventional mice (n=3 sex/condition). Although the trends in Mt1 and Mt2 were replicated in ABX samples, this only reached significance for Mt2 in males (Mt1 males: log2fc =1.15±0.6, p=0.35; Mt1 females: log2fc = 1.31±0.4, p=0.28; Mt2 males: log2fc = 1.87±0.7, p=0.03; Mt2 females: log2fc = 1.54±0.69, p=0.31). Finally, 16S rRNA sequencing showed Verrucomicrobia was more abundant in males (11.17% of gut microbes) compared to females (1.68%, p=0.005); no differences were observed in other phyla.

Conclusion

Renal gene expression is altered in GF mice. Genes regulated across tissues play roles in circadian entrainment (Per1 and Per2) and zinc-binding (Mt1 and Mt2).

Funding

  • NIDDK Support