Kidney, Pregnancy, and Transcriptomics: An Unexplored Intersection

Background: Maternal morbidity and mortality rates are unacceptably high despite advancements in healthcare, and an increasing number of women entering pregnancy suffer from comorbidities like hypertension, chronic kidney disease or diabetes. Even in healthy pregnancy, the kidneys not only adjust to the new nutritional and hemodynamic needs of the body but are also subject to physical forces elicited by the growing uterus. Despite that, there is little known about genetic and epigenetic shifts governing those changes. Very few genomic datasets describing maternal renal health during pregnancy are publicly available, and none of them are human. There is a critical need to gather information about both the baseline and injured pregnant kidney to help avoid common and preventable complications. Methods: As renal biopsies in pregnancy are exceedingly rare, we conducted the experiments in C56BL/6 mice. We used bulk RNA-seq during pregnancy day 18 and lactation day 10 and compared it to baseline gene expression. We repeated our observations after using renal ischemia-reperfusion injury (IRI, 30’ hypoxia, 24h reperfusion) to investigate changes in renal transcriptome during acute stress. Results: We identified 823 significantly deregulated genes (DEGs) when comparing baseline to pregnancy, and 705 when compared to lactation, with a significant overlap of 272 genes, suggesting long-term changes persisting through lactation. Among the pathways affected by gestation-induced DEGs were hypoxia and Il2-STAT5 signaling, suggesting ongoing stress response. We performed bilateral IRI on day 17 of pregnancy and day 9 of lactation to investigate the effects of further hypoxic injury. The pregnancies remained viable, and surprisingly there were no statistically significant differences in plasma creatinine, suggesting well-preserved kidney function. RNA-seq indicated upregulation of hundreds of genes compared to control, including several injury markers, such as Hmox1, Il-6, Cxcl1 and Ndrg1, which waned during lactation. Conclusion: Our results show that pregnancy can on its own elicit significant and long-term changes in renal transcriptomics. While renal function might not be overtly affected by the subsequent acute injury, its effects on gene expression are extensive. We hope our results prompt further studies into gestation’s effect on the kidney and aid in resolving kidney-associated complications such as preeclampsia. Funding: NIDDK Support