Renal localization and regulation of 15-hydroxyprostaglandin dehydrogenase.
Tissue prostaglandin levels are determined by both biosynthesis and catabolism. The current studies report the expression and localization of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key enzyme in prostaglandin catabolism in the kidneys. We also investigated potential interactions between 15-PGDH and cyclooxygenase (COX), a key enzyme in prostaglandin biosynthesis. Both 15-PGDH mRNA and protein levels were significantly higher in kidney cortex than in papilla, which is opposite to the expression pattern of COX-2. In situ hybridization indicated that 15-PGDH mRNA was mainly localized to the tubular epithelial cells in kidney cortex and outer medulla but not in the glomerulus or papilla. Dual immunofluorescent staining indicated that 15-PGDH was expressed in the proximal tubule, cortical, and outer medullary thick ascending limb and collecting duct but not in the macula densa or papilla. 15-PGDH levels were significantly lower in a macula densa cell line (MMDD1) than in a proximal tubule cell line. Although a high-salt diet decreased COX-2 expression in macula densa, it increased macula densa 15-PGDH expression in both mouse and rat kidneys. In MMDD1 cells, a COX-2 inhibitor increased 15-PGDH, whereas a COX-1 inhibitor had no effect. Furthermore, intense 15-PGDH immunofluorescent staining was found in both macula densa and glomerulus in COX-2 knockout mice. The intrarenal distribution of 15-PGDH and its interactions with COX-2 suggest that differential regulation of COX-2 and 15-PGDH may play an important role in determining levels of prostaglandins involved in regulation of salt, volume, and blood pressure homeostasis.
Yao
Bing
B
Division of Nephrology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Xu
Jie
J
Harris
Raymond C
RC
Zhang
Ming-Zhi
MZ
D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007672:Kidney Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D007679:Kidney Medulla / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009930:Organic Chemicals / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D000096926:Benzenesulfonamides
D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D006911:Hydroxyprostaglandin Dehydrogenases; D009930:Organic Chemicals; D011720:Pyrazoles; D017673:Sodium Chloride, Dietary; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C404729:SC 58560; C035859:15-hydroxyprostaglandin dehydrogenase; C077623:Ptgs2 protein, mouse