Renal hemodynamics and hypertension during pregnancy

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Normal pregnancy involves extensive and systemic physiological adaptations characterized by substantial volume expansion and vasodilatation. The exact mechanisms for the physiological changes have not been fully clarified, but relaxin (a corpus luteum-released hormone) has been found to play a central role in the control of hemodynamics in normal pregnancy. Inappropriate or inadequate adaptations during pregnancy may induce pathological consequences such as preeclampsia, which is characterized by new-onset hypertension and proteinuria after 20 weeks of gestation. Renal hemodynamic alterations during preeclampsia are characterized by reduced GFR and RBF by about 20-40% compared with normal pregnancies. Non-selective nitric oxide synthesis (NOS) inhibition not only blocks the elevations in GFR and RBF during normal pregnancy, but also induces hypertension and proteinuria, suggesting the essential role of nitric oxide (NO) in control of the hemodynamics in normal pregnancy and preeclampsia. GFR is normally regulated by tubuloglomerular feedback (TGF) response. The significance of TGF response in normal pregnancy and preeclampsia has not been elucidated. Specifically, whether the changes in TGF response during normal pregnancy are a consequence of systemic vessel dilatation or the cause for the increased GFR is unknown; whether the decreased GFR during preeclampsia is mediated by TGF responsiveness, which induces or is a consequence of the development of hypertension is unknown; and whether NOS1β in the macula densa mediates TGF alterations and triggers the development of hypertension during preeclampsia is unknown. All of these unidentified areas will be explored in the present proposal. We will test our hypothesis that NOS1β in the macula densa increases during normal pregnancy, which blunts TGF responsiveness that contributes to maintaining increased GFR and decreased blood pressure. During preeclampsia, factors that are released from the placenta decrease the macula densa NOS1β expression and activity, which enhances TGF responsiveness. Elevations of GFR in pregnancy are limited by the enhanced TGF response, which reduces sodium excretion, impairs pressure natriuresis, and thereby induces hypertension.