Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats

Abstract

The efficacy of gliquidone for the treatment of diabetic nephropathy was investigated by implanting micro-osmotic pumps containing gliquidone into the abdominal cavities of Goto-Kakizaki (GK) rats with diabetic nephropathy. Blood glucose, 24 h urinary protein, and 24 h urinary albumin levels were measured weekly. After 4 weeks of gliquidone therapy, pathological changes in the glomerular basement membrane (GBM) were examined using an electron microscope. Real-time PCR, western blotting, and immunohistochemistry were employed to detect glomerular expression of receptors for advanced glycation end products (RAGE) (AGER), protein kinase C b (PKCb), and protein kinase A (PKA) as well as tubular expression of the albumin reabsorption-associated proteins: megalin and cubilin. Human proximal tubular epithelial cells (HK-2 cells) were used to analyze the effects of gliquidone and advanced glycation end products (AGEs) on the expression of megalin and cubilin and on the absorption of albumin. Gliquidone lowered blood glucose, 24 h urinary protein, and 24 h urinary albumin levels in GK rats with diabetic nephropathy. The level of plasma C-peptide increased markedly and GBM and podocyte lesions improved dramatically after gliquidone treatment. Glomerular expression of RAGE and PKCb decreased after gliquidone treatment, while PKA expression increased. AGEs markedly suppressed the expression of megalin and cubulin and the absorption of albumin in HK-2 cells in vitro, whereas the expression of megalin and cubilin and the absorption of albumin were all increased in these cells after gliquidone treatment. In conclusion, gliquidone treatment effectively reduced urinary protein in GK rats with diabetic nephropathy by improving glomerular lesions and promoting tubular reabsorption.

Endothelium-dependent impairments to cerebral vascular reactivity with type 2 diabetes mellitus in the Goto-Kakizaki rat

“…The increase in these proinflammatory mediators has also been consistently reported in previous studies using the GK rat and is considered a mainstay in the T2DM condition (18,22,30). Although outside the scope of this study, previous studies have also taken urine measurement of the GK and found increased albumin, advanced glycation end products, creatinine, and protein (3,27,50,58), which is also seen in individuals with T2DM (12), further supporting…”

Nephroprotection by Hypoglycemic Agents: Do We Have Supporting Data?

“…There is a lack of studies about the renal effects of sulphonylureas on DCKD. Very recently, an experimental study has investigated the effect of implanting micro-osmotic pumps containing gliquidone into the abdominal cavities of rats with DN [ 23 ]. When compared to control or to rats treated with insulin, these authors detected that gliquidone treatment effectively reduced urinary protein.…”

Protein kinase C and protein kinase A are involved in the protection of recombinant human glucagon‐like peptide‐1 on glomeruli and tubules in diabetic rats

“…For the present study, rhGLP‐1 (7–36; beinaglutide) was purchased from Shanghai Benemae Pharmaceutical Corporation (Shanghai, China). rhGLP‐1 is an analog of native GLP‐1, and its half‐life in blood is approximately 2 h.…”

“…Blood was taken from the caudal vein, and blood glucose of >16.7 mmol/L for three consecutive days after the second STZ injection is considered the standard of a diabetic model. All the diabetic rats were fed with conventional chow for an additional 8 weeks. Then, 24 diabetic rats were divided into the three groups according to a random number‐generating table ( n = 8) as follows.…”

“…Freshly dissected kidneys were fixed overnight in 4% formaldehyde, and periodic acid–Schiff staining was carried out according to standard procedures. Semi‐quantitative scoring of glomerular sclerosis in periodic acid–Schiff‐stained slides was carried out using a masked protocol of >25 tissue sections for each group. Section immunostaining was carried out using primary antibody against PKC‐β2 (Abcam, Shanghai, China, ab32026), protein kinase A (PKA; Abcam, ab75991), nitric oxide (NO) synthase (iNOS; Abcam, ab15323), superoxide dismutase 1 (SOD1; Abcam, ab13498), megalin (Abcam, ab184676), cubilin (Abcam, ab191073), GLP‐1R (Abcam, ab218532), insulin (Abcam, ab7842), podocin (Abcam, ab50339), nephrin (Abcam, ab58968) and collagen IV (ThermoFisher, Shanghai, China, PA1‐36001).…”