Peroxisome Proliferator Activated Receptor-α Agonist Slows the Progression of Hypertension, Attenuates Plasma Interleukin-6 Levels and Renal Inflammatory Markers in Angiotensin II Infused Mice

Abstract

The anti-inflammatory properties of PPAR-α plays an important role in attenuating hypertension. The current study determines the anti-hypertensive and anti-inflammatory role of PPAR-α agonist during a slow-pressor dose of Ang II (400 ng/kg/min). Ten to twelve week old male PPAR-α KO mice and their WT controls were implanted with telemetry devices and infused with Ang II for 12 days. On day 12 of Ang II infusion, MAP was elevated in PPAR-α KO mice compared to WT (161 ± 4 mmHg versus 145 ± 4 mmHg) and fenofibrate (145 mg/kg/day) reduced MAP in WT + Ang II mice (134 ± 7 mmHg). Plasma IL-6 levels were higher in PPAR-α KO mice on day 12 of Ang II infusion (30 ± 4 versus 8 ± 2 pg/mL) and fenofibrate reduced plasma IL-6 in Ang II-treated WT mice (10 ± 3 pg/mL). Fenofibrate increased renal expression of CYP4A, restored renal CYP2J expression, reduced the elevation in renal ICAM-1, MCP-1 and COX-2 in WT + Ang II mice. Our results demonstrate that activation of PPAR-α attenuates Ang II-induced hypertension through up-regulation of CYP4A and CYP2J and an attenuation of inflammatory markers such as plasma IL-6, renal MCP-1, renal expression of ICAM-1 and COX-2.

Figure 1

Mean arterial pressure of PPAR-α KO mice [18] (•) and PPAR-α WT mice [9] (o) during control days 1–13 and treatment of Ang II days 1–12. MAP was significantly higher in Ang II-treated PPAR-α KO versus Ang II-treated WT mice (*P < 0.05).

Figure 2

Mean arterial pressure of PPAR-α KO mice [18] (•) and PPAR-α WT mice [9] (o) during control days 1–7, days 1–3 of fenofibrate treatment, and days 1–12 of Ang II + fenofibrate treatment. MAP was significantly higher in KO + Ang II + Fen versus WT + Ang II + Fen (*P < 0.05).

Figure 3

Plasma interleukin-6 levels (n = 8 per group) and renal MCP-1 levels (n = 5 per group) in control, Ang II-infused and Ang II-infused + fenofibrate-treated WT and PPAR-α KO mice. *indicates a significant increase versus control WT. λ indicates a significant increase versus control PPAR-α KO. ^†indicates a significant increase versus Ang II-infused WT mice. ^≠indicates a significant decrease versus Ang II-infused WT or PPAR-α KO mice.

Figure 4

Renal ICAM-1 and COX-2 protein expression levels relative to β-actin as markers of renal inflammation in WT and PPARα KO control, Ang II-infused and Ang II-infused + fenofibrate-treated mice. *indicates a significant increase versus control WT mice and ^#indicates a significant increase versus Ang II-infused WT mice (n = 4 per group).

Figure 5

Renal CYP4A and CYP2J protein expression levels relative to β-actin in WT and PPARα KO control, Ang II-infused and Ang II-infused + fenofibrate-treated mice. *indicates a significant increase versus control WT mice (n = 4 per group).