title: DPP8 and DPP9 expression in cynomolgus monkey and Sprague Dawley rat tissues.
abstract: Dipeptidyl peptidases (DPPs) are proteolytic enzymes that regulate many physiological systems by degrading signaling peptides. DPP8 and DPP9 are distinct from DPP4 in sequence, cellular localization and expression levels, thus implying distinct functions. However, DPP8 and DPP9 expression needs further delineation. We evaluated DPP4, DPP8 and DPP9 expression using three independent methods at the mRNA, protein, and functional levels to better understand the local physiological contribution of each enzyme. Sprague Dawley rats and cynomolgus monkeys were selected for DPP4, DPP8 and DPP9 expression profiling to represent animal species commonly utilized for drug preclinical safety evaluation. A novel Xhibit assay of DPP protease activity was applied in addition to newly available antibodies for immunohistochemical localization. This combined approach can facilitate a functional evaluation of protease expression, which is important for understanding physiological relevance. Few inter-species differences were observed. Tissue mRNA and protein levels generally correlated to functional DPP4 and DPP8/9 enzymatic activity. All three proteins were seen in epithelial cells, lymphoid cells and some endothelial and vascular smooth muscle cells. Combined DPP8/DPP9 enzymatic activity was uniformly intracellular across tissues at approximately 10-fold lower levels than non-renal DPP4. Consistent levels of each DPP were detected among most non-renal tissues in rats and monkeys. DPP4 was ubiquitous, principally detected on cell membranes of epithelial and endothelial cells and was greatest in the kidney. The expression patterns suggest that DPP8 and DPP9 may act similarly across tissues, and that their actions might in part overlap with DPP4.
authors.affiliation: Drug Safety Evaluation, Bristol-Myers Squibb Co., New Brunswick, NJ, USA. Electronic address: harstad.eric@gene.com.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Harstad
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Rosenblum
authors.forename: Mark D
authors.initials: MD
authors.lastname: Gorrell
authors.forename: William E
authors.initials: WE
authors.lastname: Achanzar
authors.forename: Lauro
authors.initials: L
authors.lastname: Minimo
authors.forename: Jiangyue
authors.initials: J
authors.lastname: Wu
authors.forename: Laura
authors.initials: L
authors.lastname: Rosini-Marthaler
authors.forename: Russell
authors.initials: R
authors.lastname: Gullo
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Ordway
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kirby
authors.forename: Kristina D
authors.initials: KD
authors.lastname: Chadwick
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Cosma
authors.forename: Carolyn F
authors.initials: CF
authors.lastname: Moyer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D007668:Kidney / Q000201:enzymology*; D008252:Macaca fascicularis; D008297:Male; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010179:Pancreas / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C527707:Dpp8 protein, rat; C527708:Dpp9 protein, rat; D018819:Dipeptidyl Peptidase 4
keywords: DPP; DPP4; DPP8; DPP9; Dipeptidyl peptidase; IgG; Monkey; PBS; Rat; cDNA; complementary DNA; dipeptidyl peptidase; immunoglobulin G; mRNA; messenger RNA; microliter; nanogram; ng; phosphate buffered saline; μL