NDT Advance Access originally published online on December 29, 2005
Nephrology Dialysis Transplantation 2006 21(4):924-934; doi:10.1093/ndt/gfk009
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Experimental Nephrology
Urinary excretions of lipocalin-type prostaglandin D2 synthase predict the development of proteinuria and renal injury in OLETF rats
1 Department of Medicine #2, Yokohama City University, Yokohama, 2 Biochemistry Research Laboratory, Central Research Institute, Maruha Corporation, Tsukuba, 3 Core Research for Evolution Science and Technology, Japan Science and Technology Corporation and Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, 4 The Department of Clinical Laboratory Medicine and Institute of Medical Science, Dokkyo University School of Medicine, Mibu and 5 Health Service Center, University of Tokyo, Tokyo, Japan
Correspondence and offprint requests to: Yoshio Uehara, MD, Health Service Center, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan. Email: uehara-2im{at}h.u-tokyo.ac.jp
Background. Otsuka Long-Evans Tokushima Fatty (OLETF) rats genetically develop diabetes which is associated with hypertension. In preliminary studies, urinary excretions of L-PGDS (lipocaline-type prostaglandin D synthase) increase before diabetic nephropathy obviously develops, and this may predict progression of renal injury following diabetes. In the present study, we attempted to define whether urinary excretions of L-PGDS behave as the predictor of development of diabetic nephropathy in OLETF rats.
Methods. We investigated alterations of urinary L-PGDS excretions during the establishment of diabetes and assessed the relationship between the L-PGDS excretions and renal function in OLETF rats. Furthermore, we treated OLETF rats with troglitazone and analysed the effects on L-PGDS metabolisms. Urinary L-PGDS was measured by immunoenzyme assay and the occurrence of L-PGDS and its mRNA in the kidney was assessed by immunohistochemistry and a PCR method.
Results. Urinary excretions of L-PGDS were significantly higher in OLETF rats than non-diabetic Long-Evans Tokushima Otsuka (LETO) rats. The excretions age-dependently increased in OLETF and this increase appeared to be due to increased glomerular permeability to L-PGDS. Messenger RNA and antigenicity of L-PGDS were demonstrated in renal tissue; however, the de novo synthesis of L-PGDS mRNA seemingly contributed to urinary L-PGDS excretions much less than glomerular filtration. Multiple regression analysis revealed that urinary L-PGDS was determined by urinary protein excretions, and not by high blood pressure per se. Conversely, urinary proteinuria in the established diabetic nephropathy was predicted by urinary L-PGDS excretions in the early stage of diabetes.
Conclusions. Urinary excretions of L-PGDS are likely to reflect the underlying increase in glomerular permeability. This property may be useful to predict forthcoming glomerular damage following diabetes in OLETF rats.
Keywords: albuminuria; diabetes; glomerular sclerosis; nephropathy; prostaglandin D synthase; proteinuria