Overproduction of transforming growth factor-beta 1 (TGF-beta 1) has been implicated in the pathogenesis of fibrotic diseases. TGF-beta 1 plays a crucial role in the accumulation of extracellular matrix (ECM) in human and experimental glomerular diseases. However, it remains unclear whether inhibition of TGF-beta 1 overproduction would suppress TGF-beta 1-induced ECM accumulation. To inhibit the overproduction of TGF-beta 1 in experimental glomerulonephritis induced by anti-Thy 1.1 antibody, we introduced antisense oligodeoxynucleotides (ODN) for TGF-beta 1 into the nephritic kidney by the HVJ-liposome-mediated gene transfer method. Sense, scrambled or reverse ODN were also introduced as controls. Transfected ODN accumulated mainly in the nuclei of mesangial cells in the glomeruli of transfected kidneys. In the antisense ODN-transfected rats, a marked decrease in expression of TGF-beta 1 mRNA was confirmed by Northern analysis. Consequently, the expression of TGF-beta 1 protein in the glomerulus was markedly reduced in the antisense ODN-transfected kidney with a comparable effect in preventing glomerular ECM expansion in experimental glomerulonephritis. In contrast, sense, scrambled and reverse ODNs failed to suppress TGF-beta 1 expression and ECM accumulation. Thus, these results suggested that inhibition of TGF-beta 1 overproduction could suppress progression to glomerulosclerosis.

Solute-free water diuretics (aquaretics) by antagonizing hydrosmotic vasopressin receptors (V2) may be useful in treating water-retaining diseases. The effects ofintravenous administration of a newly developed nonpeptide, selective V2 antagonist, OPC-31260, at doses ranging from 0.017 to 1.0 mg/kg to groups of healthy, normally hydrated men were compared with those of 0.33 mg/kg furosemide and placebo. OPC-31260 increased the hypotonic urine volume dose dependently for the first 4 h, while furosemide induced sodium diuresis for 2 h. The absolute increase in the cumulative response in the urine to the highest doses of OPC-31260 was not significantly different from that to furosemide. The higher doses of OPC-31260 rapidly lowered urine osmolality for 2 h, particularly between minutes 15 and 45 (e.g., 1.0-mg/kg dose: 63±2 mOsm/kg in urine collected between minutes 30 and 45). In a marked hypotonic diuresis, mean free water clearance of the 4-h urine increased dose proportionally into the positive range, reaching 1.80±0.21 ml/min at 1.0 mg/kg. Whereas furosemide induced marked Na and K diuresis, OPC-31260 increased urinary Na excretion only slightly. At 4 h, 0.75 and 1.0 mg/kg of OPC-31260 almost doubled the plasma arginine vasopressin; and the higher doses increased plasma osmolality and plasma Na slightly, but did not alter plasma K, blood pressure, or heart rate. OPC-31260 thus safely induced a potent aquaretic effect in men. (J. Clin. Invest. 1993. 92:2653-2659 Key words: vasopressin antagonist * aquaretic effect * urine osmolality -hyponatremia * arginine vasopressin

The present study demonstrates that (i) apoptosis is involved in the hypertonicity-induced cell death in MDCK cells; (ii) caspase-3, -8, and -9 may contribute to the apoptosis; and (iii) betaine has protective effect on the hypertonicity-induced apoptosis.

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Background: Quick estimation of creatinine clearance from serum without calculation or urine measurements may be useful in many bedside clinical circumstances. A novel formula and a nomogram for predicting creatinine clearance are presented here. Methods: We determined 24-hour creatinine clearance in 155 men and 143 women. A formula for creatinine clearance prediction from serum creatinine (Scr), age, body weight (BVV), and body mass index (BMI) was developed [men: creatinine clearance = (-0.065 Age-0.493BMI + 33)BW/Scr/14.4; women: creatinine clearance = (-0.052 Age-0.202 BMI + 21 )BW/Scr/14.4]. Variables in this formula were evaluated for suitability by multiple regression analysis. The correlation between creatinine clearance measured and creatinine clearance predicted using serum creatinine from the same subject group was high (r = 0.882). A nomogram for creatinine clearance prediction was derived from an equation that included the logarithmic transformation of age, body weight, height, and creatinine excretion instead of the original, nonlogarithmic values. Results: Correlation between measured and estimated creatinine clearance values for the nomogram was slightly lower (r = 0.879) than the r value (0.882) obtained using the original formula. However, the nomogram still has considerable reliability in creatinine clearance prediction compared with several other methods previously reported. Conclusion: The improved formula and nomogram for creatinine clearance presented here show high correlation with measured creatinine clearance. However, almost all the subjects in this study were nondiabetic patients. Therefore, the formula and the nomogram should be applied in treating nondiabetic patients; a separate formula may be needed for patients with diabetic nephropathy.