Abstract 100: Effects Of Upregulation Of Cyp4a In Dahl Salt-sensitive Rats And Ko Of Cyp4a2 And 4a3 In Ss.5 Bn Rats On The Development Of Hypertension And Renal Injury

Abstract

Mutations in CYP4F2 (rs2108622) and CYP4A11 (rs1126742) that inhibit the production of 20-HETE have been linked to hypertension in human genetic studies. We confirmed that these same variants are associated with hypertension and cognitive dysfunction in 4,286 elderly subjects in the Atherosclerosis Risk in Communities Neurocognitive Study . These studies establish that mutations in CYP enzymes that reduce 20-HETE promote hypertension, but the mechanisms remain controversial since 20-HETE has both pro- and antihypertensive actions. To address this question, we identified a homologous genetic deficiency in the formation of 20-HETE in Dahl S (SS) rats and created SS.5 BN consomic and CYP4A transgenic SS rats to restore CYP4A expression and 20-HETE production, and CYP4A2 and CYP4A3 KO rats on the rescued SS.5 BN background. Mean arterial pressure (MAP), renal and cerebral blood flow, proteinuria, and renal injury were compared in SS versus SS.5 BN and CYP4A transgenic SS rats and in SS.5 BN versus CYP4A2 and CYP4A3 KO rats. MAP increased from 117±2 to 158±5 mmHg (n=34) in SS rats fed a high salt (HS) diet for 3 weeks. Proteinuria rose from 50±4 to 403±30 mg/day. MAP increased less, from 108 + 5 to 133 + 5 mmHg (n=7) in CYP4A1 transgenic SS rats and from 109 + 2 to 132 + 2 mmHg (n=23) in SS.5 BN rats. Proteinuria (141±15 and 169±11 mg/day), glomerular injury, and renal fibrosis were all significantly reduced in the CYP4A transgenic and SS.5 BN rats compared to SS rats. KO of CYP4A2 had no effect on MAP (134 + 2 mmHg, n=23) or proteinuria (248 + 23 mg/day) relative to SS.5 BN rats fed an HS diet for 3 weeks. In contrast, MAP and proteinuria were elevated to 148 + 3 mmHg and 350 + 23 mg/day in CYP4A3 KO rats (n=23). The myogenic response of renal and cerebral arteries and autoregulation of RBF and CBF were impaired in SS and CYP4A3 KO rats but were intact in CYP4A transgenic SS rats, SS.5 BN and CYP4A2 KO rats. These findings indicate that a deficiency in the formation of 20-HETE that impairs the myogenic response of renal and cerebral arteries, autoregulation of RBF and CBF, and increases glomerular capillary pressure, promotes the development of hypertension, proteinuria, and renal injury in genetically susceptible individuals and SS rats.