Project Grant R01DK136989

INVESTIGATING THE EFFECT OF DYSREGULATED VITAMIN D METABOLISM ON KIDNEY DEVELOPMENT FOLLOWING PRETERM BIRTH - PROJECT SUMMARY/ABSTRACT VITAMIN D DEFICIENCY IS COMMON IN NEONATES BORN PRETERM AND IMPLICATED THE PATHOGENESIS DISEASE IN SEVERAL ORGANS, SUCH AS THE LUNG AND RETINA. IN THE KIDNEY, VITAMIN D SUPPLEMENTATION CLEARLY PREVENTS THE LOSS OF A PODOCYTES IN ANIMALS WITH GLOMERULAR DISEASE. THE PODOCYTE IS A TERMINALLY DIFFERENTIATED CELL VITAL TO THE INTEGRITY OF THE GLOMERULAR FILTRATION BARRIER, AND PODOCYTE LOSS LEADS TO CHRONIC KIDNEY DISEASE (CKD). PRETERM BIRTH IS ASSOCIATED WITH BOTH INCREASED PODOCYTE LOSS AND CKD. DESPITE THE KIDNEY BEING A MAJOR SOURCE FOR THE ACTIVE FORM OF VITAMIN D, LITTLE IS KNOWN ABOUT EITHER THE EFFECT OF PERINATAL VITAMIN D DEFICIENCY ON THE DEVELOPING KIDNEY OR ITS ASSOCIATION WITH LONG TERM KIDNEY DISEASE. THE GOAL OF THIS PROPOSAL IS TO UNDERSTAND THE VITAMIN D PATHWAY IN PRETERM NEONATES AND THE ROLE OF VITAMIN D IN PODOCYTE HEALTH IN A PRETERM MODEL. THIS GOAL IS MOTIVATED BY OUR EXCITING OBSERVATIONS OF DYSREGULATION OF SEVERAL COMPONENTS OF VITAMIN D METABOLISM IN A MOUSE MODEL OF PRETERM BIRTH. PRETERM BIRTH ALTERED THE EXPRESSION OF GENES INVOLVED IN VITAMIN D METABOLISM IN THE KIDNEY SUGGESTING A LOCAL REDUCTION OF ACTIVE FORM VITAMIN D (1,25 VITAMIN D) AS WELL AS DECREASED NPHS1 EXPRESSION. NPHS1 PROMOTES PODOCYTE DIFFERENTIATION, AND ITS EXPRESSION IS REGULATED BY VITAMIN D. THE CHANGES IN GENE EXPRESSION IN THE PRETERM KIDNEYS SUPPORT A NOVEL MECHANISM FOR THE LOWER PODOCYTE NUMBER AND CKD SEEN IN PRETERM NEONATES. WE HYPOTHESIZE THAT DYSREGULATION OF VITAMIN D METABOLISM (CYP27B1, CYP24A1) IN THE PRETERM KIDNEY CAUSES A LOCAL DEFICIENCY OF 1,25 VITAMIN D, RESULTING IN REDUCED NPHS1 EXPRESSION, IMPAIRED PODOCYTE DIFFERENTIATION, DECEASED PODOCYTE DENSITY AND ALBUMINURIA. POTENTIAL THERAPEUTIC OPTIONS TO OVERCOME THE VITAMIN D DYSREGULATION IN PRETERM NEONATES COULD INCLUDE 1,25 VITAMIN D SUPPLEMENTATION OR MATERNAL 25 VITAMIN D ADMINISTRATION. TO TEST OUR HYPOTHESIS, WE PROPOSE TWO INDEPENDENT AIMS INVESTIGATING NEONATE AND MATERNAL VITAMIN D DYSREGULATION. IN AIM 1, WE WILL FULLY CHARACTERIZE VITAMIN D PATHWAY BY MEASURING SYSTEMIC AND LOCAL (KIDNEY) VITAMIN D METABOLITES ALONG WITH A KEY REGULATORS OF VITAMIN D METABOLISM. TO DETERMINE THE INDEPENDENT EFFECT OF ACTIVATED VITAMIN D PATHWAY ON THE PODOCYTE, WE WILL TREAT PRETERM MICE JUST AFTER BIRTH WITH ACTIVE VITAMIN D OR VITAMIN D ANTAGONISTS. OUR PRIMARY OUTCOME WILL BE ALBUMINURIA AND SECONDARY OUTCOMES WILL INCLUDE PODOCYTE DENSITY, URINARY PODOCYTE LOSS AND GLOMERULAR NUMBER. WE WILL ASSESS THE MOLECULAR MECHANISMS BY TESTING TRANSCRIPTIONAL CHANGES AT BOTH SINGLE-CELL AND WHOLE KIDNEY RESOLUTION. IN AIM 2, WE WILL DETERMINE THE CONTRIBUTION OF MATERNAL VITAMIN D STATUS ON THE KIDNEY HEALTH OF THE OFFSPRING BORN PRETERM. WE WILL MODIFY THE VITAMIN D STATUS OF THE DAM WITH A VITAMIN D DEFICIENT DIET OR PROVIDE A HIGH DOSE OF 25 VITAMIN D TO THE MOTHER JUST BEFORE BIRTH OF THE PRETERM PUPS TO DETERMINE THE EFFECT ON ALBUMINURIA IN THE OFFSPRING. FINDINGS FROM THIS STUDY WILL PROVIDE THE BASIS FOR A FEASIBLE CLINICAL TRIAL USING NUTRITIONAL MODIFICATIONS IN NEONATES OR MOTHERS TO IMPROVE KIDNEY HEALTH OUTCOMES OF THOSE BORN PRETERM.