Nephrectomy and high-salt diet inducing pulmonary hypertension and kidney damage by increasing Ang II concentration in rats

Background Pulmonary hypertension (PH) is a common complication in patients with chronic kidney disease (CKD), affecting prognosis. However, the pathogenesis is not clear, and the lack of a stable animal model is a significant factor. Methods In this study, a rat model of chronic kidney disease with pulmonary hypertension (CKD-PH) was developed through 5/6 nephrectomy combined with a high-salt diet. The model’s hemodynamics and pathological changes in multiple organs were dynamically assessed. Lung tissues and serum were collected from the model rats to measure the expression of ACE2, the expression levels of vascular active components related to the renin-angiotensin-aldosterone system (RAAS), and changes in the serum metabolic profile of the model. Results After 14 weeks post-surgery, the CKD-PH rat model exhibited significant changes in hemodynamic parameters indicative of pulmonary arterial hypertension, along with alterations such as right ventricular hypertrophy. However, no evidence of pulmonary vascular remodeling was observed. An imbalance in the renin-angiotensin-aldosterone system was identified in the CKD-PH rat models. Downregulation of ACE2 expression was observed in pulmonary tissues. The serum metabolic profile of the CKD-PH rat models showed distinct differences compared to the sham surgery group. Conclusions The development of pulmonary arterial hypertension in CKD-PH rats may be primarily attributed to the disruption of the renin-angiotensin-aldosterone system (RAAS), coupled with a decrease in ACE2 expression in pulmonary vascular endothelial tissues and metabolic disturbances. ### Competing Interest Statement The authors have declared no competing interest. * ACE : Angiotensin converting enzyme ALD : Aldosterone AQP1 : Aquaporin 1 BNP : B-type natriuretic peptide CKD : Chronic kidney disease CO : Cardiac output COPD : Chronic obstructive pulmonary disease CTEPH : Chronic thromboembolic pulmonary hypertension DAG : Diacylglycerol DBP : Diastolic blood pressure EF : Ejection fractions eSphK1 : Erythrocyte-specific sphingosine kinase 1 FC : Fold change HETEs : Hydroxyeicosatetraenoic acids IPAH : Idiopathic pulmonary arterial hypertension KEGG : Kyoto Encyclopedia of Genes and Genomes mABP : mean arterial blood pressure OAT1 : Organic anion transporter 1 PADN : Percutaneous pulmonary artery denervation PAECs : Pulmonary arterial endothelial cells PASMCs : Pulmonary arterial smooth muscle cells PAT/PET : Pulmonary acceleration time/pulmonary ejection time PH : Pulmonary hypertension RAAS : Renin-angiotensin-aldosterone system ROC : Receiver-operating-characteristic RVH : Right ventricular hypertrophy RV/(LV+S) : right ventricular/(left ventricular + septum) RVSP : Right ventricular systolic pressure SBP : Systolic blood pressure SNS : Sympathetic nervous system SP : Spironolactone SV : Stroke volume S1P : Sphingosine 1-phosphate TMAO : Trimethylamine-N-oxide TRPC6 : Transient receptor potential canonical channel XPB : Xeroderma pigmentosum group B complementing protein