Hercule Hantz C, Wang Mong-Heng, Oyekan Adebayo O
Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
J Physiol. 2003 Sep 15;551(Pt 3):971-9. doi: 10.1113/jphysiol.2003.049981. Epub 2003 Jul 11.
20-Hydroxyeicosatetraenoic acid (20-HETE), a major renal eicosanoid, regulates renal function and contributes to renal responses following withdrawal of nitric oxide (NO). However, the role of 20-HETE-synthesizing isoforms in renal function resulting from NO inhibition is unknown. The present study evaluated the role of cytochrome (CYP)4A1, -4A2 and -4A3 isoforms on renal function in the presence and absence of NO. Antisense oligonucleotides (ASODN) to CYP4A1, -4A2 and -4A3 reduced 20-HETE synthesis and downregulated the expression of CYP4A isoforms in renal microsomes. Nomega-L-nitromethyl arginine ester (L-NAME, 25 mg kg(-1)), an inhibitor of NO production, increased mean arterial blood pressure (MABP, Delta = +18 to 26 mmHg), reduced renal blood flow (RBF, Delta = -1.8 to 2.9 ml min(-1)), increased renal vascular resistance (RVR, Delta = +47 to 54 mmHg ml(-1) min(-1)), reduced glomerular filtration rate (GFR), but increased sodium excretion (UNaV). ASODN to CYP4A1 and -4A2 but not -4A3 reduced basal MABP and RVR and increased basal GFR, while ASODN to CYP4A2 significantly reduced basal UNaV suggesting a differential role for CYP4A isoforms in the regulation of renal function. ASODN to CYP4A2 but not -4A1 or -4A3 blunted the increase in MABP by L-NAME (38 +/- 9 %, P < 0.05). ASODN to CYP4A1, -4A2 and -4A3 attenuated the reduction in RBF and the consequent increase in RVR by L-NAME with a potency order of CYP4A2 = CYP4A1 > CYP4A3. ASODN to CYP4A1 and -4A2 but not -4A3 attenuated L-NAME-induced reduction in GFR, but ASODN to all three CYP4A isoforms blunted the L-NAME-induced increase in UNaV (CYP4A3 > CYP4A1 >> CYP4A2). We conclude from these data that CYP4A isoforms contribute to different extents to basal renal function. Moreover, CYP4A2 contributes greatest to haemodynamic responses while CYP4A3 contributes greatest to tubular responses following NO inhibition. We therefore propose that NO differentially regulates the function of CYP4A1, -4A2, and -4A3 isoforms in the renal vasculature and the nephron.
20-羟基二十碳四烯酸（20-HETE）是一种主要的肾脏类花生酸，可调节肾功能，并在一氧化氮（NO）撤除后对肾脏反应起作用。然而，NO抑制后，20-HETE合成同工型在肾功能中的作用尚不清楚。本研究评估了细胞色素（CYP）4A1、-4A2和-4A3同工型在有或无NO情况下对肾功能的作用。针对CYP4A1、-4A2和-4A3的反义寡核苷酸（ASODN）可减少20-HETE的合成，并下调肾微粒体中CYP4A同工型的表达。NO生成抑制剂Nω-硝基-L-精氨酸甲酯（L-NAME，25 mg·kg⁻¹）可升高平均动脉血压（MABP，Δ = +18至26 mmHg），降低肾血流量（RBF，Δ = -1.8至2.9 ml·min⁻¹），增加肾血管阻力（RVR，Δ = +47至54 mmHg·ml⁻¹·min⁻¹），降低肾小球滤过率（GFR），但增加钠排泄（UNaV）。针对CYP4A1和-4A2而非-4A3的ASODN可降低基础MABP和RVR，并增加基础GFR，而针对CYP4A2的ASODN可显著降低基础UNaV，这表明CYP4A同工型在肾功能调节中具有不同作用。针对CYP4A2而非-4A1或-4A3的ASODN可减弱L-NAME引起的MABP升高（38±9%，P < 0.05）。针对CYP4A1、-4A2和-4A3的ASODN可减弱L-NAME引起的RBF降低及随之而来的RVR增加，效力顺序为CYP4A2 = CYP4A1 > CYP4A3。针对CYP4A1和-4A2而非-4A3的ASODN可减弱L-NAME引起的GFR降低，但针对所有三种CYP4A同工型的ASODN均可减弱L-NAME引起的UNaV增加（CYP4A3 > CYP4A1 >> CYP4A2）。从这些数据我们得出结论，CYP4A同工型对基础肾功能有不同程度的贡献。此外，NO抑制后，CYP4A2对血流动力学反应的贡献最大，而CYP4A3对肾小管反应的贡献最大。因此，我们提出NO对肾血管系统和肾单位中CYP4A1、-4A2和-4A3同工型的功能有不同调节作用。
