D28-16 Transcriptomic Remodeling of Kidneys in Preclinical Models of Pulmonary Hypertension and Right Heart Failure

Rationale

Pulmonary hypertension (PH) is a progressive pulmonary vascular disease characterized by elevated pulmonary artery pressures leading to right ventricular failure (RVF) and death. Growing evidence suggests that PH is associated with extrapulmonary manifestations. The Renin-Angiotensin-Aldesterone System (RAAS) plays a central role in PH, due to the fundamental connection between the heart, lungs, liver, and kidneys. Currently, there is a paucity of data on changes in the kidneys secondary to PH and RVF. We hypothesized that severe PH and RVF in pre-clinical models is associated with remodeling in the kidneys.

Methods

PH and RVF were induced in male Sprague Dawley rats with either monocrotaline (MCT) (60 mg/kg; subcutaneous; 4-week protocol; n = 6) or Sugen with hypoxia (SuHx) (20 mg/kg; 3-week hypoxia 10%O2, 2-week normoxia; n = 6). Saline treated rats served as control (n = 6). Serial echocardiography and terminal cardiac catheterization were performed. RV hypertrophy index, RV systolic pressure, and RV function were recorded. Kidneys were processed for histology and bulk RNA sequencing and bioinformatics analysis was conducted.

Results

MCT and SuHx rats developed severe PH and RVF as demonstrated by significantly increased RV systolic pressure and RV hypertrophy index, and significantly reduced RV function (p < 0.05 for all parameters). Subsequent transcriptomic analysis on the kidneys revealed transcriptomic remodeling in the diseased rats. There were a total of 13 unique pathways in the MCT rats, 16 in the SuHx rats, and 10 common pathways significant between both models. Common upregulated pathways included apoptosis and several inflammatory pathways including, IL-6/JAK/STAT3 signaling and interferon gamma response. Additionally, a total of 463 genes specific to MCT, 675 genes specific to SuHx, and 97 genes common between both rat models were significant compared to control rats (padj<0.05). Of the common genes, top significantly downregulated genes included Spns2, Prima1, and Nrep among others. Top significantly upregulated genes included Hmox1, Mmp8, and Mup5 among others. Notably, Hmox1, which was the overall most significantly upregulated gene in both models, is involved in hypertension and oxidative stress pathways, as well as a regulator of inflammation.

Conclusion

In preclinical models of PH and RVF, there is extensive transcriptomic remodeling in kidneys. Specifically, the evidence of upregulation in inflammatory pathways and genes, such as Hmox1, in the kidneys may serve as potential therapeutic targets.

This abstract is funded by: R01HL161038