Fumarate Reduced Mean Arterial Blood Pressure and Improved Renal Outcomes in DOCA/salt Hypertension

Abstract

The mitochondria, through the tricarboxylic (TCA) acid cycle, converts organic molecules into energy that drives intricate renal blood‐pressure regulatory functions. The TCA cycle intermediaries regulate the metabolic state of the mitochondria and by extension, the redox status of the cell. Recently, fumarase, a major TCA cycle enzyme that converts fumarate to malate, has been linked to L‐arginine metabolism and implicated in the pathophysiology of Dahl‐salt sensitive hypertension. This study aimed to investigate the role of fumarase and L‐arginine in deoxycorticosterone (DOCA)/salt hypertension, a non‐genetic model of hypertension. Hypertension was induced in uninephrectomised rats with DOCA (25 mg/kg) + 1 % NaCL. Mean arterial blood pressure was measured in conscious rats via carotid cannulation. Biochemical and western blot analyses were carried out on homogenized kidney fractions. Fumarate reduced arterial blood pressure (198±5 vs 167±7 mmHg, P<0.01). There were no changes in urinary output and sodium excretion in fumarate‐treated DOCA rats (P>0.05). Superoxide dismutase and catalase activities were higher in the cortex, but not the medulla of DOCA‐hypertensive rats and were exacerbated by fumarate (P<0.01). There was a selective increase in catalase activity in the medulla of fumarate‐treated DOCA‐hypertensive rats (P<0.01). Fumarate also reduced urinary protein excretion in DOCA‐hypertensive rats (23.6 %, P<0.05). Fumarate evoked a selective increase in nitric oxide in the medulla (34.1±2.9 vs 47.3±2.8 nM/μg, P<0.05) of DOCA‐hypertensive rats. Consistent with this, Fumarate also tended to increase arginase activity in the cortex but not the medulla of DOCA‐hypertensive rats. However, there was an increase in expression TGF‐β, an index of fibrosis, in DOCA‐hypertensive rats, which was paradoxically increased in fumarate‐treated rats (P>0.05). In conclusion, fumarate attenuated the hypertension and renal injury but not the fibrosis in DOCA/salt hypertension by mechanisms involving selective reduction of L‐arginine metabolism in the medulla and amelioration of renal oxidative stress.Support or Funding InformationNational Institute of Health grant HL03674 and G12 MD0076056Mean arterial blood changes after 21‐day administration of fumarate to DOCA/salt induced hypertensive rats. Control (n=8), DOCA (n=8), fumarate (n=8). a=P<0.001 when compared to control; b=P<0.01 when compared to DOCA group.Figure 1Nitric oxide produced in homogenized kidneys (cortex and medulla) of DOCA salt induced hypertensive rats after 21‐day fumarate (1 mg/kg) administrationa=P<0.05 when compared to control.Figure 2