The role of androgens in the production of 20-hydroxyeicosatetraenoic acid (20-HETE) was determined in the kidney of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The renal production of 20-HETE and blood pressure were higher in males than in females at 9 weeks of age. The renal production of 20-HETE was significantly greater in male SHR than in male WKY, whereas it was significantly lower in female SHR than in female WKY. The differences in the renal production of 20-HETE were consistent with the cytochrome P-450 4A protein levels. Plasma free-testosterone levels in male SHR were twice as high as those in male WKY. Castration and treatment with the androgen receptor antagonist, flutamide, reduced blood pressure, the renal production of 20-HETE, and P-450 4A protein levels in both strains. The renal production of 20-HETE was significantly lower in castrated SHR than in castrated WKY. These results indicate that the renal production of 20-HETE and the expression of P-450 4A have gender and strain-differences, and high levels of plasma androgens induce the expression of P-450 4A and the production of 20-HETE in the kidney of male SHR. The androgen-induced production of 20-HETE may be associated with hypertension in male SHR.

Androgens↗

PubMed2003

Regulation of cytochrome P-450 4A activity by peroxisome proliferator-activated receptors in the rat kidney.

The localization of cytochrome P-450 4A, peroxisome proliferator-activated receptor (PPAR) alpha, and PPARgamma proteins, and the inducibility of P-450 4A expression and activity by PPAR agonists were determined in the rat kidney. The expressions of these proteins in isolated nephron segments were evaluated by immunoblot analysis, and the production of 20-hydroxyeicosatetraenoic acid (20-HETE) was measured as P-450 4A activity. P-450 4A proteins were expressed predominantly in the proximal tubule (PT), with lower expression in the preglomerular arteriole (Art), glomerulus (Glm), and medullary thick ascending limb (mTAL), but their expression was not detected in the inner medullary collecting duct (IMCD). PPARalpha protein was expressed in the PT and mTAL, and PPARgamma protein was expressed in the IMCD and mTAL. Treatment with clofibrate, the PPARalpha agonist, increased P-450 4A protein levels and the production of 20-HETE in microsomes prepared from the renal cortex, whereas treatment with pioglitazone, the PPARgamma agonist, affected neither of them. These results indicate that PPARalpha and PPARgamma proteins are localized in different nephron segments and the inducibility of P-450 4A expression and activity by the PPAR agonists correlates with the nephron-specific localization of the respective PPAR isoforms.

Animals↗

PubMed2002

Biphasic vasodilator action of troglitazone on the renal microcirculation.

Recent studies have demonstrated that thiazolidinediones, novel antidiabetic compounds that improve the insulin sensitivity, lower BP and decrease urinary protein excretion. However, neither the target vasculature nor the underlying mechanism for their actions is well understood. In this study, the action of troglitazone (Tro), a thiazolidinedione compound, on the glomerular afferent (Af-Arts) and efferent (Ef-Arts) arterioles, crucial vascular segments to the control of glomerular hemodynamics, were directly examined. Rabbit Af-Arts or Ef-Arts were microdissected from the superficial cortex and perfused at constant pressure. Increasing doses of Tro (10(-8) to 10(-5) M) were added to both the bath and lumen of preconstricted arterioles. In Af-Arts, Tro caused dose-dependent and biphasic dilation. Tro at 10(-5) M increased the diameter by 28 +/- 6% (n = 8, P < 0.01) until 20 min, with the diameter remaining at this level for 60 min, and then Tro began to dilate Af-Arts again. At 120 min, Tro at 10(-5) M further increased the diameter by 23 +/- 4% (n = 6). Disrupting the endothelium had no effect on either dilation (n = 7 or n = 5). Pretreatment with SKF 96365 (50 microM), which inhibits both voltage- and receptor-operated calcium channels, abolished the early-phase dilation without affecting the late-phase dilation; 20 or 120 min after adding Tro at 10(-5) M, the diameter increased by 4 +/- 2% (n = 7) or 28 +/- 3% (n = 6), respectively. In contrast to Af-Arts, Tro caused monophasic dilation in Ef-Arts; Tro at 10(-5) M did not cause significant dilation until 80 min, and at 120 min the diameter increased by 37 +/- 4% (n = 5). These results suggest that in the Af-Art Tro has biphasic endothelium-independent vasodilator action, which is partly mediated by an inhibition of calcium influx. This vasodilator action may play a role in the BP-lowering effect of Tro. In addition, by dilating the postglomerular Ef-Art, Tro may decrease the glomerular capillary pressure and hence the excretion of urinary protein.

Angiotensin II↗