Abstract: SA-OR02
Stat5b SNP Reduces Sexual Dimorphism of Renal Gene Expression and Protects against Acute Injury
Session Information
- AKI: An Inflamed State of the Union
October 26, 2024 | Location: Room 5, Convention Center
Abstract Time: 04:40 PM - 04:50 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Jankowski, Jakub, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Lee, Hye kyung, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Hennighausen, Lothar, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
Background
The extent of the single nucleotide polymorphisms’ (SNP) impact on disease vulnerability is not well understood. Two Stat5b Y665 SNPs, Y665F and Y665H, have been found by genome sequencing of leukemia patients. They are thought to respectively increase or attenuate STAT5b activity but have not been confirmed as a disease driver.
Methods
Using base editing, we developed mice mimicking the two SNPs and investigated their phenotype. We saw an increased infiltration of CD3+ cells in the kidney tissue of the Y665F strain using immunohistochemistry, suggesting increased vulnerability to development of inflammation. To investigate, we used 30’ bilateral kidney ischemia-reperfusion injury (IRI) model and measured serum creatinine after 24 hours. To elucidate involvement of JAK/STAT pathway, we performed kidney RNA-seq analysis in WT, Y665F and Y665H strains, including male and female mice, before and after IRI.
Results
Y665F males had lower creatinine levels than controls (mean 0.66 vs 1.23, p<0.001, n=8), suggesting protection against IRI. In contrast Y665F females displayed no statistically significant difference in plasma creatinine compared to control (0.79 vs 1.04 respectively, n=5). Similar effect was absent in Y665H mice, indicating protective effect of STAT5b activation in an IRI setting. RNA-seq revealed 582 deregulated genes (DEGs) between male WT and Y665F mice at the baseline, but no statistically significant DEGs were found in females. After IRI, 1801 DEGs were found in male mice, but only six in females. Similar number of sexually dimorphic genes is present in WT and Y665F strains at the baseline (1269 vs 1290 respectively), but not after injury (1790 vs 733). Y665F DEGs include genes involved in JAK/STAT signaling and linked to kidney health and development such as Il15, Xdh, Sepp1 or Prickle1, hinting at potential mechanisms of protection. We did not observe differences in Stat5b mRNA nor STAT5b and CD3 immunohistochemical staining after injury in WT or Y665F mice, suggesting long-term changes in renal gene transcription programming rather than acutely altered injury response.
Conclusion
Those results strongly indicate that Stat5b Y665 SNP has a sexually dimorphic, renoprotective effect. This work highlights the far-reaching effects of a singular SNPs and lays foundation of personalized medicine approaches incorporating patient’s genome.
Funding
- NIDDK Support