Pathophysiological Roles of Peroxisome Proliferator Activated Receptor (PPAR) on Development and Progression of Chronic kidney diseases -Search for a New Therapeutic Target for Chronic Kidney Diseases-

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(1)Pathogenetic actions of Peroxisome Proliferator Activated Receptor (PPAR) on glomerular cells: In rat mesangial cells in culture, high ambient glucose(25mM), especially when fluctuated time by time, promoted Vascular Endothelial Growth Factor(VEGF) production and DNA synthesis, which is inhibited by treatment of the cells with a thiazolizinedione, a PPAR, agonist. In the kidney specimens from 18 type 2 patients with early stage of diabetic nephropathy, glomerular VEGF messenger RNA expression determined by in situ hybridization is well correlated with neovasculization at the vascular pole and mesangial matrix area^<1)> (glomerular sclerosis) ^<6)>. We presented a case of POEMS (Crow-Fukase) syndrome with Type 2 diabetes, which was associated with elevated plasma VEGF level, but no sign of diabetic nephropathy^<8)>. We also measured plasma VEGF concentration in Type 2 diabetic patients with normo-, micro, and macro-albuminuria, the results of which showed that the presence of DN is n … More ot associated with an elevation of circulating plasma VEGF concentration2). These results suggest that overproduction of VEGF in situ in the kidney may play a local pathogenetic role in early-stage DN, which is dependent on PPAR,and PKC.(2)Establishment of gene transfer system using adenovirus vector and application for model animals with renal diseases : We established a system of mRNA measurement by RT-real time PCR(light-cycler) and that of gene transfer system using adeno-virus vector encoding PPAR,, and PAF-AH cDNA (AdhPPAR,,nd AdhPAF-AH) which are confirmed to express respective mRNA and protein in various culture cell systems.First, AdhPAF-AH was trasfected to a nephrosclerosis model animal (SHC rat), which resultantly inhibited nephrosclerosis through PAF-AH expression in the liver and transferred to the kidney on HDL particles12). Estabulishment of kidney specific, effective gene transfer system would promote application of AdhPPAR,、,nd AdhPAF-AH for gene therapy of various model animals for common renal disease such as diabetic nephropathy or IgA nephropathy.(3)Pathogenetic roles of PPAR and its related factors for the pathophysiology in animal models with renal diseases: IgA nephropathy model mice (HIGA mouse) were feeded with,inolenic acid (an, 3 series poly-unsaturated fatty acid (PUFA))-or linolic acid (, 6 series PUFA) which are also possible ligands for PPAR. Feeding with,inolenic acid compared to that with linolic acid inhibited proteinuria, renal dysfunction(increase in plasma creatinine) and glomerular sclerotic change^<13)>, suggesting a potential involvement in pathogenesis and a potential therapeutic target of PPAR for IgA nephropathy. The physiological roles of prostanoids (PUFA-derived autacoid) in the kidney are tested using their receptor knoch-out mce, suggesting that salt-sensitivity is partly dependent upon prostanoids^<10)>, but ischemic acute renal failure^<3)>. In additon, direct micro-dilution into the remnant kidney in unilateral nephrectomizen, salt-loaded rats of an anti-sense oligonucleotide to type 1 angiotensin II receptor(AT1) amelionate proteinuria and patho-histological changes without changing blood pressure in spontaneous hypertensive rats (SHR) ^<11)>, supporting the concept that angiotensin II locally produced plays a significant roles in progression of renal dysfunction via ATI receptor signals.(4)Clinical studies targeted for cardio-vascular events in chronic kidney diseases : We registered about 600 HD patients and cross-sectionally examined the clinical parameters responsible for incidence of cardiovascular, which showed that the strongest predictor for events is inflammation (CRP) followed by diabetes and so forth and that use of ARB and/or ACE inhibitors inaddition of BW, serum albumin and body weight representative for good nutritional state and effectiveness of hemodialysis (HD) (Kt/V) improved life prognosis^<5)>. Intake of, inolenic acid improved CRP in the control population, but not in the HD patients (manuscript in preparation), explaining partly poor prognosis due to cardiovascular events of HD patients. Less