Project Grant R01HL171997

PANX1-PIEZO1 INTERACTIONS REGULATE RENIN RELEASE - || ABSTRACT HYPERTENSION IS THE MOST COMMON PATHOLOGICAL INDICATOR FOR CARDIOVASCULAR DISEASES. THE KEY BIOLOGICAL SYSTEM THAT REGULATES BLOOD PRESSURE IS THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS); ITS DYSREGULATION AT ALMOST ANY LEVEL CAN PRECIPITATE HYPERTENSION. FOR THIS REASON, PATHWAYS IN THE RAAS CAN BE MANIPULATED FOR PHARMACOLOGICAL INTERVENTIONS (E.G., ACE INHIBITORS). IN THIS APPLICATION WE INTERROGATE THE RELEASE OF RENIN, THE RATE LIMITING STEP OF ACTIVATION OF THE RAAS, FROM JUXTAGLOMERULAR (JG) CELLS IN THE AFFERENT ARTERIOLES, AND PROVIDE EXCITING PRELIMINARY DATA TO DEMONSTRATE A NOVEL MECHANICALLY-SENSITIVE SIGNALING AXIS. IN PARTICULAR, THE APPLICATION IS FOCUSED ON OUR RECENT WORK INVOLVING PANX1 CHANNELS IN JG CELLS, AND HOW THEY MAY BE COUPLED TO THE BONA FIDE MECHANICALLY SENSITIVE PIEZO1 CHANNELS SPECIFICALLY FOUND IN JG CELLS. INTERESTINGLY, WE HAVE IDENTIFIED A ROLE FOR ESTROGEN RECEPTOR ALPHA THAT MAY PROVIDE A LEVEL OF PROTECTION WHEN COUPLED WITH PIEZO1. BASED ON OUR PRELIMINARY DATA, WE HYPOTHESIZE RENIN RELEASE CAN BE DICTATED BY MECHANICALLY SENSITIVE PIEZO- PANX1 COMPLEXES IN JG CELLS THAT ARE REGULATED BY SEX DEPENDENT AND INDEPENDENT FEEDBACK. WE PROPOSE THREE AIMS TO TEST THIS: 1. PROTEIN KINASE A (PKA) REGULATION OF PANX1 CHANNELS; 2. CHANGES IN AFFERENT ARTERIOLE PRESSURE IS SENSED BY PIEZO1 AND CAN REGULATE PANX1 AND 3. ESTROGEN RECEPTOR A REGULATES PIEZO CHANNEL ACTIVITY. IN ORDER TO ACCOMPLISH THESE AIMS, WE HAVE DERIVED NOVEL MOUSE LINES (INCLUDING PANX1T20A AND REN1D- CRE/PIEZO1FL/FL) AND STATE-OF-THE-ART TECHNIQUES (E.G., ISOLATED RENIN SECRETING CELLS, ISOLATED KIDNEY PERFUSION, CALCIUM IMAGING ON KIDNEY SLICES). THIS APPLICATION IS COMPOSED OF AN INTERNATIONALLY RENOWNED TEAM OF EXPERTS, WITH ALL PROPOSED KNOCKOUT MICE BEING ON HAND, AND ROBUST PRELIMINARY DATA. WE BELIEVE THE DATA WILL PROVIDE AN IMPORTANT NEW LAYER OF REGULATION IN THE RAAS CAPABLE OF PHARMACOLOGICAL INTERVENTION.