REVERSAL OF UNILATERAL URETERAL OBSTRUCTION LEADS TO SALT‐SENSITIVE HYPERTENSION

Abstract

Hypertension is a major cardiovascular disease and 50% of the hypertensive population has salt‐sensitive hypertension. There is mounting evidence that a long‐term consequence of acute kidney injury is increased risk for salt‐sensitive hypertension and chronic kidney disease (CKD). Animal models to study the pathophysiological basis for salt‐sensitive hypertension that follows occurrence of kidney injury are lacking. In the current study, we used a reversal unilateral ureteral obstruction (RUUO) model to study long‐term kidney injury consequences to cause salt‐sensitive hypertension. In this model, we removed the ureteral obstruction 10 days following UUO surgery in 8–10 week old male C57BL/6J mice and divided them into four groups (n=5–6/group): Sham‐Normal Salt Diet, Sham‐8% NaCl Salt Diet, RUUO‐Normal Salt Diet, and RUUO‐8% NaCl Diet. We removed the clip form the ureter day10 day which is a time point the UUO mice demonstrate marked renal fibrosis, inflammation, tubular injury, and lower vascular density. At day 10, the mice were fed a normal or 8% NaCl diet for 4 weeks. Weekly blood pressure was measured till the end of the protocol followed by terminal urine and kidney tissue collection for biochemical, histological, immunohistological, and gene expression studies. There was a progressive and steady rise in systolic blood pressure to 130±5 mmHg in RUUO‐8% NaCl diet group compared to other groups that averaged 113–118 mmHg. Interestingly, RUUO‐8% NaCl group had 50% higher albuminuria compared to Sham‐8% NaCl Salt Diet group. We also demonstrated significant increases in renal mRNA expression of adhesion molecules ICAM and VCAM in RUUO‐8% NaCl diet group compared Sham‐8% NaCl Salt Diet. Most importantly, we demonstrated that RUUO‐8% NaCl diet group had 30% lower vascular density in the outer medullary area and 16% lower cortical vascular density compared to RUUO‐8% NaCl diet group. Overall, these findings present a new animal model to study kidney injury to salt‐sensitive hypertension. In addition, development of salt‐sensitive hypertension and kidney injury in RUUO mice is associated with decreased renal vascular density.