Stereo-isomer specific induction of renal cell apoptosis by synthetic muramyl dipeptide (N-acetylmuramyl-L-alanyl-D-isoglutamine).
The cytotoxicity of bacterial cell wall components, muramyl dipeptide (synthetic N-acetylmuramyl-L-alanyl-D-isoglutamine; L,D-MDP) and lipopolysaccharide (LPS), was investigated in several kidney cell lines. MDP and LPS were toxic to rabbit and monkey kidney cells, MDP was toxic to canine kidney cells, but not to human or porcine kidney cells. Notably, L,D-MDP was >100-fold more cytotoxic/microg than the D,D-MDP and L,L-MDP, as well as LPS. L,D-MDP and analogs containing L,D-MDP were the most widely cytotoxic of the MDP tested. The MDP-induced cytotoxicity was characterized as apoptosis by DAPI staining and DNA laddering. The acute rabbit kidney (RK13) cell apoptosis (cell death in < 5 h) induced by apical or basal application of MDP was associated with glutamate (Glu) release, decreased gamma-glutamyltranspeptidase (GGT) and acidosis and was suppressed by Indomethacin, Naproxen and Curcumin. The cytotoxic activity of L,D-MDP was decreased significantly by 24 h incubation in human sera. Aged (> 2 year-old) rabbits that apparently failed to quickly clear and excrete a uveitogenic dose of MDP within 24 h died in I week. The results indicate that minute amounts (5 ng/ml) of MDP containing L-alanyl-D-isoglutamine can induce renal cell apoptosis in vitro and support MDP-induced kidney cytotoxicity in rabbits. Also, the results indicate that MDP in sera can be detected utilizing the RK13 cell bioassay and that failure to rapidly clear and excrete L,D-MDP is associated with uveitis and death in aged rabbits.
Department of Ophthalmology, Louisiana State University Health Sciences Center, Shreveport 71130-3932, USA. mlangf@lsuhsc.edu
Marlyn P
MP
Langford
Dequan
D
Chen
Tomas C
TC
Welbourne
Thomas B
TB
Redens
James P
JP
Ganley
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000737:chemistry / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D016718:Arachidonic Acid / Q000494:pharmacology; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology* / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011817:Rabbits; D013237:Stereoisomerism; D013552:Swine; D013997:Time Factors; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D000276:Adjuvants, Immunologic; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D016718:Arachidonic Acid; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D004247:DNA; D015237:Dinoprost; D011451:Prostaglandin-Endoperoxide Synthases; D005723:gamma-Glutamyltransferase; D015232:Dinoprostone