Contribution of prolyl hydroxyl binding proteins (PHD) to MYD88/NFkB pathways in Nitric Oxide deficiency‐induced hypertensive renal injury

Abstract

Oxidative stress and associated inflammation, features of hypertension and kidney disease, involve many mediators that include Nrf2, a transcription factor, the primary cellular defense against oxidative stress, MYD88, an adaptor protein implicated in NFkB‐mediated inflammation. PHD, oxygen sensor in hypoxia is intricately linked to NO. This study evaluated the role played by PHD and its association with Nrf2, MYD88 and NFKB in hypertension‐induced renal injury.Adult rats were placed on LNNA, inhibitor of NO synthase and/or DMOG, an inhibitor of PHD. Blood pressure (BP) was determined on Days 1, 4, 7, and 14 and 24‐hour urine collected for protein excretion. Kidneys were collected to determine expression of PHD1 and PHD2, Nrf2, p65, and MYD88 in nuclear fractions. KIM‐1 expression, index of tubular damage, was assessed in whole kidneys. Plasma TNFa and IL‐1b levels, markers of inflammation, were measured by ELISA. Renal generation of oxidant species was evaluated as xanthine (3,5,10 mg/kg)‐induced generation of H2O2. LNNA, inhibitor of NO synthase increased BP (35%, P<0.05), kidney weight (15%, P<0.05), protein excretion (3.5‐fold, P<0.05) and KIM‐1 expression (3.8‐fold, P<0.05). DMOG blunted the increases. LNNA also reduced PHD2 (20%) but not PHD1 expression or Nrf2 expression. There was increased nuclear expression of p65 (34%, P<0.05) and MYD88 (32%, P<0.05) and increased TNFa and IL‐1b (P<0.05) in LNNA‐treated rats. DMOG blunted these effects. Renal production of H2O2 by xanthine was greater (P<0.05) in LNNA‐treated rats. These data suggest a role for PHD2 in hypertensive renal injury and inflammation induced by NO deficiency. The accompanying changes in MYD88/p65 expression and cytokine production confirm the ongoing inflammatory process. However, despite the increase in production of reactive oxygen species, Nrf2 does not appear to play a part in NO deficiency‐induced cardiovascular effect.Support or Funding InformationNational Institutes of Health grant 5G12 MD007605