KIOM‐79, an Inhibitor of AGEs–Protein Cross‐linking, Prevents Progression of Nephropathy in Zucker Diabetic Fatty Rats

Abstract

Advanced glycation end products (AGEs) have been implicated in the development of diabetic complications, including diabetic nephropathy. KIOM-79, an 80% ethanolic extract obtained from parched Puerariae Radix, gingered Magnolia Cortex, Glycyrrhiza Radix and Euphorbia Radix, was investigated for its effects on the development of renal disease in Zucker diabetic fatty rats, an animal model of type 2 diabetes. In vitro inhibitory effect of KIOM-79 on AGEs cross-linking was examined by enzyme-linked immunosorbent assay (ELISA). KIOM-79 (50 mg/kg/day) was given to Zucker diabetic fatty rats for 13 weeks. Body and kidney weight, blood glucose, glycated hemoglobin, urinary albumin and creatinine excretions were monitored. Kidney histopathology, collagen accumulation, fibrinogen and transforming growth factor-beta 1 (TGF-β1) expression were also examined. KIOM-79 reduced blood glucose, kidney weight, histologic renal damage and albuminuria in Zucker diabetic fatty rats. KIOM-79 prevented glomerulosclerosis, tubular degeneration, collagen deposition and podocyte apoptosis. In the renal cortex, TGF-β1, fibronectin mRNA and protein were significantly reduced by KIOM-79 treatment. KIOM-79 reduces AGEs accumulation in vivo, AGE–protein cross-linking and protein oxidation. KIOM-79 could be beneficial in preventing the progression of diabetic glomerularsclerosis in type 2 diabetic rats by attenuating AGEs deposition in the glomeruli.

Effects of Chebulic Acid on Advanced Glycation Endproducts-Induced Collagen Cross-Links

“…In the present study, BSA glycated with glycolaldehyde, Glycol-BSA was prepared, and was then employed to induce cross-links to collagen, which was measured using an ELISA system. 18) Glycated BSA with glycolaldehyde in the absence of collagen was employed to induce AGEs including cross-links, and the incorporation of [ 14 C] lysine into BSA was used to measure cross-link activity in our previous study. CA showed significantly potent activity in inhibiting cross-links to collagen compared with AG in the present assay, whereas AG as a positive control gave similar magnitude of potency against cross-links in ELISA assay (IC 50 , 67.8± 2.5 mM) and the previously reported radioactivity assay (IC 50 , 21.3± 1.4 mM).…”

“…The breaking assay on Glycol-BSA induced cross-links to collagen was performed according to the method by Kim et al 18) with some modifications. To confirm the breaking activity on Glycol-BSA induced cross-links to collagen, 1 mg/mL of Glycol-BSA was pre-incubated on 1.5 mg/mL of collagen for 24 h, and was then incubated in either the presence or absence of ALT-711 or CA at 37°C for 16 h. In detail, HRP labeled Glycol-BSA was pre-incubated on collagen-coated 96-well plates for 4 h, and the Glycol-BSA induced complexes with collagen were incubated in either the presence or absence of ALT-711 (Suchem Pharma Co., Wenzhou, China) or CA at 37°C for 16 h. After the unattached Glycol-BSA was washed in 0.05% PBST, breaking levels were detected using TMB substrate.…”

KIOM-79 prevents xylose-induced lens opacity and inhibits TGF-beta2 in human lens epithelial cells cultured under high glucose

“…KIOM-79, which is a mixture of ethanol extracts from parched Puerariae radix, gingered Magnolia cortex, Glycyrrhiza radix, and Euphorbia radix, was developed based on the known function of each herb in treating diabetes. It has inhibitory effects on the development of renal disease in animal models of type 1 and type 2 diabetes (Kim et al, 2009). Previous studies have also shown that KIOM-79 has anti-diabetic effects, such as protection of betacells, reduced glucose in non-obese type 2 diabetic rats, inhibition of AGEs formation in vitro, and anti-inflammatory effects (Jeon et al, 2006;Kim et al, 2006Kim et al, , 2007aKim et al, , 2008aKim et al, ,b, 2009Kang et al, 2007).…”

Screening System of Blocking Agents of the Receptor for Advanced Glycation Endproducts in Cells Using Fluorescence

“…[7][8][9] In our previous study, 700 plant extracts and phytochemicals were tested for inhibition of AGE formation by incubating glucose and bovine serum albumin (BSA) for 14 d; several extracts were shown to prevent diabetic complications, specifically nephropathy, cataract formation, and retinopathy in experimental animal models. [10][11][12] …”

“…[7][8][9] In our previous study, 700 plant extracts and phytochemicals were tested for inhibition of AGE formation by incubating glucose and bovine serum albumin (BSA) for 14 d; several extracts were shown to prevent diabetic complications, specifically nephropathy, cataract formation, and retinopathy in experimental animal models. [10][11][12] RAGE is a member of the immunoglobulin superfamily that consists of three extracellular immunoglobulin-like domains (i.e., V, C1, and C2), a transmembrane helical domain, and a short intracellular, negatively charged C-terminal tail that is indispensable for RAGE signaling. 13,14) The soluble form of RAGE (sRAGE) indirectly blocks AGE-RAGE binding.…”