We examined the potential contributions of oxidative stress and thromboxane A2 (TXA2) to the development of regional heterogeneity in hypertensive glomerular injury using stroke-prone spontaneously hypertensive rats (SHRSP), an animal model of human essential hypertension. We also examined the effect of antioxidant treatment on the regional expression of thromboxane synthase (TXAS) mRNA using a microdissection method. Increases in the glomerular expression of TXAS mRNA were observed in the SHRSP at 15 weeks of age compared with those in the age-matched normotensive control Wistar-Kyoto (WKY) rats: 2.4-fold and 3.1-fold in the superficial and juxtamedullary glomeruli, respectively (P < 0.05). The heme oxygenase-1 mRNA expression was markedly increased (greater than eightfold, P < 0.05) in both the superficial and juxtamedullary glomeruli in the SHRSP compared with the expression in the WKY rats. In contrast to our expectations, the treatment of SHRSP with tempol (a superoxide dismutase mimetic) significantly (P < 0.05) increased the TXAS mRNA expression in the superficial glomeruli and did not improve the histological injury or albuminuria, which were both aggravated. Moreover, ozagrel (a TXAS inhibitor) had a suppressive effect on the TXAS mRNA expression and significantly (P < 0.05) improved the histological injury. These results indicated that although TXA2 and oxidative stress are linked to each other, TXA2 rather than oxidative stress may be a better therapeutic target to improve hypertensive glomerular injury.

Cell adhesion molecule 1 (CADM1) is an immunoglobulin superfamily member strongly expressed on renal tubular epithelia in the urinary tract. Enzymatic cleavage of its ectodomain increases in chronic kidney disease (CKD), and is assumed to contribute to tubulointerstitial lesion formation. Because the cleaved ectodomain fragments are likely to be released into the urine, a sandwich enzyme-linked immunosorbent assay (ELISA) system for urinary CADM1 was developed using two anti-ectodomain antibodies. Urinary CADM1 concentrations in patients with CKD based on various forms of glomerulonephritis and nephropathy (n = 127) were measured. A total of 44 patients (35%) had elevated CADM1 concentrations over the normal upper limit (362 pg/mL), with a mean of 1,727 pg/mL. Renal biopsy specimens of all patients were pathologically scored for tubulointerstitial lesions using epithelial degeneration, interstitial inflammation, and fibrosis. There were no correlations between urinary CADM1 concentrations and pathological scores or any widely used renal markers, including glomerular filtration rate (GFR), but there was a weak inverse correlation between pathological scores and GFR (R2 = 0.292). Notably, this correlation gradually increased in patients with increasing CADM1 concentrations, and reached a maximum R2 (0.899) at a cutoff of 1,569 pg/mL. The results of this study suggest that urinary CADM1 is a useful marker indicating tubulointerstitial damage from elevated GFR levels in CKD.

症例は53歳の男性でインスリン抵抗性糖尿病を有するWerner症候群の患者である. 空腹時インスリン値は24μU/mlと高値であり, euglycemic hyperinsulinemic clamp時のブドウ糖注入率 (GIR) は3.70mg/kg/minと低下していた. やせ型 (BMI14.2kg/m2), 体脂肪率の少ない (4.9%) 患者であったが, pioglitazone 30mg/日を投与したところ, 投与12週間後にGIRは5.20mg/kg/minと上昇し, 空腹時血糖値は187mg/dlから105mg/dlに低下, 1.5-anhydroglucitolは2.3μg/mlから4.4μg/mlと上昇した. 空腹時インスリン値は投与8週, 12週後に27μU/ml, 22μU/mlと変化は認めなかった. 血糖値の低下はインスリン感受性改善によるものと考えられ, 体脂肪の少ない本患者でもpioglitazoneが有効と考えられた. 以上のことより, 本患者では一般的に提唱されているthiazolidinedione系薬物の作用機序 (脂肪細胞のPPARγを活性化する) とは異なったメカニズムが働いていることが示唆された.

2型糖尿病の病態では、ASK-JNK経路が酸化ストレスと小胞体ストレスの両者に深く関与する重要な経路であり、インスリン抵抗性改善のkey pathwayの可能性であることが考えられた。また、このASK-JNK経路を調節することが、2型糖尿病患者に対しての治療標的になりえる可能性があり、そのことが将来的に糖尿病性合併症の予防・進展抑制につながっていく可能性を期待している。