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Stimulation of Urinary TGF-ß and Isoprostanes in Response to Hyperglycemia in Humans

Tracy A. McGowan^*, Stephen R. Dunn, Bonita Falkner, and Kumar Sharma^*,

^* Center for Diabetic Kidney Disease, Cell and Molecular Biology of Kidney Disease-Dorrance Hamilton Research Laboratories, and Center for Hypertension, Division of Nephrology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania

Address correspondence to: Dr. Kumar Sharma, Thomas Jefferson University, Department of Medicine, 353 Jefferson Alumni Hall, 1020 Locust Street, Philadelphia, PA 19107. Phone: 215-503-6950; Fax: 215-923-7212; E-mail: kumar.sharma{at}jefferson.edu

TGF-ß and oxidant stress have been considered to play key roles in the pathogenesis of diabetic vascular complications; however, the stimulus for these factors in humans is not clear. The purpose of this in vivo study was to determine whether transient hyperglycemia in humans is sufficient to increase renal production of TGF-ß1 and urinary isoprostanes in normal humans. A hyperglycemic clamp procedure was performed on 13 healthy volunteers. An infusion of glucose was delivered to maintain the plasma glucose between 200 and 250 mg/dl for 120 min. Timed urine samples, collected on an overnight period before the study, at each void on completion of the procedure, and the following overnight, were assayed for TGF-ß1, F2-isoprostanes, and creatinine. Plasma samples were assayed for TGF-ß1 before and at timed intervals throughout hyperglycemia. Mean baseline TGF-ß1 in plasma was 4.57 ± 0.22 ng/ml, and no change in plasma TGF-ß1 levels was detected throughout the hyperglycemia period. Baseline urine TGF-ß1 was 4.14 ± 1.16 pg/mg creatinine. The fractional urine samples showed a sharp increase in TGF-ß1 excretion in the 12-h period after exposure to hyperglycemia, with a mean peak TGF-ß1 of 30.43 ± 8.05 pg/mg (P = 0.002). TGF-ß1 excretion in the subsequent overnight urine sample was not different from baseline (4.62 ± 1.21 pg/mg). Urinary isoprostanes increased from a baseline of 4.92 ± 0.74 to 13.8 ± 3.37 ng/mg creatinine. It is concluded that 120 min of hyperglycemia in normal humans is sufficient to induce an increase in renal TGF-ß1 and isoprostane production.