Prostaglandin (PG) E2 has diverse actions in the kidney affecting renin release, vascular tone, and epithelial functions. PGE2 is synthesized from arachidonic acid by the sequential actions of phospholipases, cyclooxygenases, and PGE synthases. To date, two microsomal PGE synthases (mPGES1 and mPGES2) have been identified that generate PGE2 from endoperoxides with high affinity and specificity. These enzymes have different sequences and patterns of regulation. While the functions of mPGES1 and mPGES2 in the kidney have not been defined, our preliminary studies indicate that: (1) mPGES1 and mPGES2 are both highly expressed in the kidney, (2) renal PGE2 synthesis can be detected in the absence of mPGES1, and (3) mPGES1 does not account for all of the actions of PGE2 in the kidney or in extra-renal tissues. Based on these data, we hypothesize that mPGES1 and mPGES2 have discrete functions to regulate regional synthesis of PGE2 providing a mechanism for independent control of the paradoxical actions of PGE2 in the kidney. After its synthesis, PGE2 is rapidly metabolized. We previously found that 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the primary pathway for PGE2 metabolism in vivo and that its actions are essential for remodeling the ductus arteriosus at birth. However, a physiological role for 15-PGDH in the kidney has not been demonstrated. In preliminary studies, we showed that renin mRNA expression is enhanced and blood pressures are elevated in 15-PGDH-deficient mice. We therefore posit that 15-PGDH is a critical pathway for extinguishing the renal actions of PGE2. In the kidney, the dominant effect of 15- PGDH is to regulate the activity of PGE2 at the juxta-glomerular apparatus (JGA). Using mouse models, we will define the functions of the genes that regulate the activity of PGE2 in the kidney by carrying out the following specific aims: 1. To identify the genes in the PGE2 pathway controlling renin expression and release. 2. To define the capacity of mPGE synthases to modulate kidney function. 3. To define the impact of PGE2 metabolism by 15-PGDH on renal functions.
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