PPAR‐α Activation Decreases Pro‐Inflammatory Cytokines in the Plasma, while increasing Renal Expression of CYP4A and Decreasing COX2

Peroxisome proliferator‐activated receptor‐alpha (PPAR‐α) activation by fenofibrate reduces blood pressure and sodium retention during DOCA‐salt hypertension. PPAR‐α activation also reduces the expression of inflammatory cytokines, such as interleukin‐6 (IL‐6). Fenofibrate induces CYP4A and increase 20‐ HETE production. Although 20‐HETE is a potent vasoconstrictor, it has been shown to inhibit sodium transport and promote natriuresis at the renal tubule. This study determined whether the administration of fenofibrate would reduce blood pressure by attenuating plasma pro‐inflammatory cytokines, IL‐6, IL‐17 and TNF‐α and renal expression of COX2, while increasing expression of renal CYP4A during DOCA‐salt hypertension. We performed uni‐nephrectomy on 6–8 week old male Swiss Webster mice and implanted biotelemetry devices. Mice were divided into DOCA (50 mg) and salt (1 % NaCl and 0.1% KCl); and DOCA‐salt plus fenofibrate (500 mg/kg/day in corn oil, intragastrically) and collected mean arterial pressure for 7 days. Fenofibrate significantly decreased mean arterial pressure on day 7 of DOCA‐salt by 30 + 15 mmHg with no significant reduction on heart rate. Fenofibrate significantly decreased plasma IL‐6, IL‐17 and TNF‐α by 40%, 80% and 90%, respectively. In kidney homogenates, fenofibrate increased CYP4A expression by 40% and decreased COX2 by 70%. There was no difference in renal CYP2C23 and sEH expression between the groups. Our results suggest that the blood pressure lowering effect of PPAR‐α activation by fenofibrate involves the reduction of pro‐inflammatory cytokines IL‐6, IL‐17 and TNF‐α in the plasma and increased 20‐HETE natriuretic effects during DOCA‐salt hypertension. PPAR alpha activation may also protect the kidney against renal injury induced by DOCA treatment via decreased COX2 –induced inflammation.