Project Grant R00HL157549

NOX2-DERIVED OXIDATIVE STRESS PRODUCED BY T CELLS CONTRIBUTES TO THE DEVELOPMENT OF MATERNAL SYNDROME IN THE DAHL SALT-SENSITIVE RAT. - PROJECT ABSTRACT NOX2-DERIVED OXIDATIVE STRESS PRODUCED BY T CELLS CONTRIBUTES TO THE DEVELOPMENT OF MATERNAL SYNDROME IN THE DAHL SALT-SENSITIVE RAT. PREECLAMPSIA (PE) IS A PREGNANCY-SPECIFIC DISORDER THAT IS CHARACTERIZED BY HYPERTENSION AND PROTEINURIA (MATERNAL SYNDROME) DEVELOPING AFTER THE 20TH WEEK OF GESTATION. PE IS THE LEADING CAUSE OF MATERNAL MORBIDITY AND MORTALITY IN THE UNITED STATES, AFFECTING ABOUT 5-7% OF PREGNANCIES. FURTHERMORE, WOMEN WITH PREEXISTING HYPERTENSION OR CHRONIC KIDNEY DISEASE HAVE AN INCREASED RISK FOR DEVELOPING PE. WITH RATES OF PE RISING IN THE UNITED STATES, THE EXACT MECHANISM(S) RESPONSIBLE FOR THE PATHOGENESIS OF THE DISEASE REMAIN UNDETERMINED. THE CURRENT NOTION OF THE PATHOGENESIS OF PE IS THOUGHT TO BE A TWO-STEP PROCESS: 1) IMPROPER PLACENTATION AND REMODELING OF THE SPIRAL ARTERIES AND 2) DEVELOPMENT OF MATERNAL SYNDROME. CURRENT ANIMAL MODELS REQUIRE EITHER A SURGICAL OR PHARMACOLOGIC INTERVENTION TO DEVELOP PE-LIKE PHENOTYPES; HOWEVER, THESE MODELS ARE NOT CAPABLE OF INVESTIGATING THE FIRST STEP IN THE DISEASE PROCESS. OUR PRELIMINARY DATA DEMONSTRATE THAT THE DAHL SALT-SENSITIVE (SS) RAT IS JUST SUCH AN ANIMAL MODEL TO HELP INVESTIGATE MECHANISMS OF PE SINCE IT SPONTANEOUSLY DEVELOPS PE WHILE REMAINING ON A LOW SALT (0.4% NACL) DIET. THE PRESENT STUDIES WILL TEST THE CENTRAL HYPOTHESIS THAT MATERNAL SYNDROME IN DAHL SS RATS IS AN OUTCOME OF IMPROPER PLACENTATION LEADING TO THE INFILTRATION OF T CELLS INTO KIDNEY AND PLACENTAL TISSUES CAUSING SUBSEQUENT RELEASE OF REACTIVE OXYGEN SPECIES (ROS) THAT CONTRIBUTES TO ENDOTHELIAL DYSFUNCTION AND THE DEVELOPMENT HYPERTENSION AND RENAL DAMAGE. TO TEST THIS HYPOTHESIS, THREE SPECIFIC AIMS ARE PROPOSED. AIM 1 WILL FIRST TEST THE HYPOTHESIS THAT T CELL DERIVED ROS (NOX2-DERIVED) CAUSES MATERNAL SYNDROME IN DAHL SS RATS UTILIZING A NOVEL SPLENOCYTE TRANSFER APPROACH. AIM 2 WILL DEMONSTRATE THAT T-CELL DERIVED ROS RESULTS IN ENDOTHELIAL DYSFUNCTION THAT DEVELOPS IN MATERNAL SYNDROME. INTERESTINGLY, THIS MATERNAL SYNDROME PHENOTYPE OCCURS IN A DIVERGENT FASHION WITH ABOUT 50% OF SS RATS DEVELOPING MATERNAL AND THE OTHER HALF ARE PROTECTED. AIM 3 WILL INVESTIGATE THE RENAL DYSFUNCTION THAT OCCURS DURING PE AND THE INCREASED RISK OF DEVELOPING CHRONIC KIDNEY DISEASE LEADING TO INCREASED MORTALITY IN DAHL SS RATS. THIS MATERNAL SYNDROME PHENOTYPE IS CONSISTENT WITH WHAT IS OBSERVED IN CLINICAL SETTINGS, AND THIS MODEL PROVIDES A UNIQUE OPPORTUNITY TO STUDY THE WHOLE DISEASE PROCESS OF PE. COMPLETION OF THE STUDIES IN THIS PROPOSAL WILL ESTABLISH THE INTERACTION BETWEEN T CELL-DERIVED ROS AND ENDOTHELIAL FUNCTION IN PE TO BETTER UNDERSTAND THE UNDERLYING MECHANISMS OF PE.