Abstract: TH-PO090
Altered Signaling Pathways in ZSF1 Rats with AKI and Metabolic Disease
Session Information
- AKI: Mechanisms - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Ma, Li-Jun, CVMR-PH, Janssen, Johnson & Johnson, Spring House, Pennsylvania, United States
- Du, Fuyong, CVMR-PH, Janssen, Johnson & Johnson, Spring House, Pennsylvania, United States
- Kalyana-Sundaram, Shanker, CVMR-PH, Janssen, Johnson & Johnson, Spring House, Pennsylvania, United States
- Meng, Rong, CVMR-PH, Janssen, Johnson & Johnson, Spring House, Pennsylvania, United States
- Xu, Jialin, Discovery Statistics, TMEDS, SDS, Janssen, Johnson & Johnson, Spring House, Pennsylvania, United States
- Pocai, Alessandro, CVMR-PH, Janssen, Johnson & Johnson, Spring House, Pennsylvania, United States
- Nawrocki, Andrea R., CVMR-PH, Janssen, Johnson & Johnson, Spring House, Pennsylvania, United States
Background
Acute kidney injury (AKI) is a common cause of kidney failure and mortality. No treatments are approved for AKI. We reported at ASN in 2022 (TH-PO088) that obese and diabetic ZSF1 rats subjected to ischemia-reperfusion injury (IRI) exhibit more severe renal function decline and slower renal function recovery relative to lean non-diabetic rats. To further understand the molecular mechanisms underlying the observed phenotypes, RNA-Seq and pathway analysis were performed.
Methods
RNA-Seq was conducted in obese and lean rat kidneys (n=4-6 each) collected at 24 hours (acute phase of AKI) or 7 days post IRI (repairing phase of AKI). Control group included rats without surgery and sham surgery. Pathway enrichment analysis for the differentially regulated genes was carried out using KEGG and Ingenuity Pathway Analysis (IPA). Enrichment p-values were adjusted for multiple hypothesis testing using the Benjamini-Hochberg method (p values < 0.05). Further, the correlation analysis was performed to study the potential association between the plasma creatine levels and the expression level of differentially expressed genes.
Results
Principal component analysis showed that the transcriptomic profiling data from RNA-seq was clustered into three distinct groupings: (1) Obese/IRI 24 h, (2) Lean/IRI 24 h and (3) rest of the groups (Lean/IRI/7d, or Obese IRI/7d or control groups). We observed that 509 and 180 genes were significantly dysregulated in obese vs lean rats at 24 hours and 7 days post IRI, respectively. Pathway analysis revealed profound downregulation of the de novo NAD synthesis related tryptophan metabolism pathway and activation of proinflammatory interleukin-17 (IL-17) signaling pathway at 24 hours post IRI. Interestingly, IL-17 signaling pathway remained significantly activated even at 7 days post IRI. The expression of genes in the IL-17 pathway correlated with plasma creatinine levels.
Conclusion
Our study suggests de novo NAD synthesis and IL-17 as potential pathways involved in AKI progression and highlights novel therapeutic approaches for AKI.
Funding
- Commercial Support – Johnson & Johnson