Inhibiting albumin glycation attenuates dysregulation of VEGFR-1 and collagen IV subchain production and the development of renal insufficiency

Abstract

CW. Inhibiting albumin glycation attenuates dysregulation of VEGFR-1 and collagen IV subchain production and the development of renal insufficiency. Am J Physiol Renal Physiol 292: F789 -F795, 2007. First published October 3, 2006; doi:10.1152/ajprenal.00201.2006.-Glomerular cells in culture respond to albumin containing Amadori glucose adducts (the principal serum glycated protein), with activation of protein kinase C-␤1, increased expression of transforming growth factor (TGF)-␤1, the TGF-␤ type II signaling receptor, and the extracellular matrix proteins ␣1(IV) collagen and fibronectin and with decreased production of the podocyte protein nephrin. Decreasing the burden of glycated albumin in diabetic db/db mice significantly reduces glomerular overexpression of TGF-␤1 mRNA, restores glomerular nephrin immunofluorescence, and lessens proteinuria, mesangial expansion, renal extracellular matrix protein production, and increased glomerular vascular endothelial growth factor (VEGF) immunostaining. In the present study, db/db mice were treated with a small molecule, designated 23CPPA, that inhibits the nonenzymatic condensation of glucose with the albumin protein to evaluate whether increased glycated albumin influences the production of VEGF receptors (VEGFRs) and type IV collagen subchains and ameliorates the development of renal insufficiency. Renal levels of VEGF and VEGFR-1 proteins and serum creatinine concentrations were significantly higher and renal levels of ␣3(IV) collagen and nephrin proteins and endogenous creatinine clearance values were significantly lower in control diabetic than in age-matched nondiabetic (db/m) mice. These changes were significantly attenuated in db/db littermate mice treated from 9 to 18 wk of age with 23CPPA. The findings indicate that inhibiting excess nonenzymatic glycation of serum albumin improves renal molecular biology abnormalities and protects against the development of renal insufficiency in the db/db mouse. diabetes; glycated albumin GLOMERULAR CELLS IN CULTURE respond, in a euglycemic milieu, to albumin modified by Amadori glucose adducts with activation of protein kinase C-␤ 1 and extracellular signal-regulated kinase, upregulation of the transforming growth factor (TGF)-␤ system, increased production of extracellular matrix proteins, and reduced expression of the podocyte protein nephrin (4,6,12,13,15,19). The relevance of these observations to the pathogenesis of diabetic nephropathy in vivo is supported by results of animal studies, which have shown that treatment of diabetic db/db mice with a small molecule that inhibits the nonenzymatic glycation of serum albumin decreases the glomerular mRNA expression of TGF-␤1, prevents depletion of glomerular nephrin (quantified by immunofluorescence), ameliorates mesangial expansion and mRNA overexpression of the extracellular matrix proteins ␣ 1 (IV) collagen and fibronectin, and lessens the urinary excretion of albumin and type IV collagen (measured as mg/24 h and ng/24 h, respectively) (9, 14). This treatment has also b...

Anti-Glycation and Anti-Albuminuric Effects of GLY-230 in Human Diabetes

“…Urine albumin values were lower at study end compared to baseline in all of the microalbuminuric patients receiving GLY-230, whether or not they were being treated with an ACE inhibitor or AR blocker. This encouraging finding replicates results in experimental animals [26,27] and, in the prompt response to a 2-week course of study drug, resembles the precedent established for reduction of albuminuria with relatively short-term therapeutic intervention reported with the renin inhibitor aliskiren [30]. In that study of 15 patients with type 2 diabetes, aliskiren reduced the urine albumin/creatinine ratio after 2–4 days of treatment [30]; patients were given furosemide, but previous medications were discontinued before enrollment, whereas in the present study patients being treated with an ACE inhibitor or ARB continued to receive these agents.…”

“…Coupled with the finding that glycated albumin decreases nephrin production [20] and that GLY-230 restores glomerular nephrin in genetically diabetic mice [26,27], it is reasonable to postulate that the lessening of albuminuria accompanying reduction in glycated albumin reflects improved podocyte health/nephrin production, although renal biopsy, which is obviously far beyond the scope of the present study, would be required for confirmation.…”

“…Subjects were reasonably well matched with respect to HbA1c levels, which did not change significantly between screening and end of study, consistent with stable glycemic status during this 5- to 6-week interval. GLY-230 has been shown to reduce glycated albumin despite prevailing hyperglycemia in animals with experimental diabetes, consistent with an effect on the nonenzymatic glycation of albumin that operates independent of glycemic control [16,26,27]. The reduction in glycated albumin reflects a decrease in the rate of formation, which has been estimated at ≈1.3% of protein per day at 5.5 m M glucose (0.25%/day/m M glucose), with the Amadori product representing a constant fraction of the glucose concentration over the range of 3.5–35 m M glucose [29].…”

“…Evidence supporting the participation of glycated albumin in renal disease in human diabetes includes the observations that the concentration of glycated albumin associates independently with nephropathy and vascular dysfunction, and corresponds with severity of renal involvement [23,24,25]. In preclinical studies in diabetic db/db mice, GLY-230 significantly reduced plasma glycated albumin, decreased urine albumin excretion, restored glomerular nephrin, downregulated TGF-β 1 and VEGF overexpression, and ameliorated matrix accumulation, histomorphometric changes, and the development of renal insufficiency [16,26,27]. Phase I single rising dose clinical studies of GLY-230 in normal human subjects have shown no adverse events or laboratory abnormalities at doses of 50–1,000 mg (IND #72218, Serial No.…”

Reduction in VEGF Protein and Phosphorylated Nephrin Associated with Proteinuria in Adriamycin Nephropathy Rats

“…Very recent studies suggested that VEGF secreted from podocytes might act as an autocrine factor on both itself and endothelial cells [13]. The upregulation of VEGF expression was detected in various human and experimental renal diseases [14, 15], and the blockage targeted to VEGF signaling could reduce proteinuria in several models of diabetic nephropathy [16, 17]. These results implied that VEGF played important deleterious roles in the occurrence and development of proteinuria.…”