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

Abstract

TGF-␤ 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-␤1 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-␤1, F2-isoprostanes, and creatinine. Plasma samples were assayed for TGF-␤1 before and at timed intervals throughout hyperglycemia. Mean baseline TGF-␤1 in plasma was 4.57 ؎ 0.22 ng/ml, and no change in plasma TGF-␤1 levels was detected throughout the hyperglycemia period. Baseline urine TGF-␤1 was 4.14 ؎ 1.16 pg/mg creatinine. The fractional urine samples showed a sharp increase in TGF-␤1 excretion in the 12-h period after exposure to hyperglycemia, with a mean peak TGF-␤1 of 30.43 ؎ 8.05 pg/mg (P ‫؍‬ 0.002). TGF-␤1 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-␤1 and isoprostane production.

Pirfenidone for Diabetic Nephropathy

“…20 Similarly, in an animal model pirfenidone conferred a benefit to glomerular histology and reduced gene expression of matrix molecules in the diabetic db/db mouse without lowering albuminuria. 19 Urine levels of TGF-␤ have been found to be increased in patients with diabetic nephropathy 12,29,30 and may reflect ongoing renal production. 12 However, in the study presentedhereurinelevelsofTGF-␤werenotsignificantlyaffectedby pirfenidone; this may be due to the wide variability of urine levels in patients and/or the small sample size.…”

Insulin Resistance, Oxidative Stress, and Podocyte Injury: Role of Rosuvastatin Modulation of Filtration Barrier Injury

“…The urinary levels of 15-isoprostane F 2t (also known as 8-epi-PGF2 2 α or 8-iso-PGF2 2 α ) were used for the assessment of oxidative stress in experimental models of diabetes [[31,][32]]. It has been shown that unmetabolized cyclooxygenase-derived prostaglandins in the urine are almost exclusively from their local formation in the kidney [30].…”

Effect of resveratrol and rosuvastatin on experimental diabetic nephropathy in rats

“…The urinary total TGF-b 1 levels were determined by enzymelinked immunosorbent assays using commercially available kits according to the manufacturer's instructions. TGF-b 1 values were presented as picograms per mg of creatinine, to correct variations of urine amount [27]. The antioxidant and oxidative stress status were measured following our previous report [28].…”