Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in diabetes mellitus. Oxidative stress, insulin resistance and pro-inflammatory cytokines have been shown to play an important role in pathogeneses of renal damage on type 2 diabetes mellitus (DM). Inonotus obliquus (IO) is a white rot fungus that belongs to the family Hymenochaetaceae; it has been used as an edible mushroom and exhibits many biological activities including anti-tumor, anti-oxidant, anti-inflammatory and anti-hyperglycemic properties. Especially the water-soluble Inonotus obliquus polysaccharides (IOPs) have been previously reported to significantly inhibit LPS-induced inflammatory cytokines in mice and protect from streptozotocin (STZ)-induced diabetic rats. In order to identify the nephroprotective effects of low molecular weight of IOP fraction (LIOP), from the fruiting bodies of Inonotus obliquus, high-fat diet (HFD) plus STZ-induced type 2-like diabetic nephropathy C57BL/6 mice were investigated in this study. Our data showed that eight weeks of administration of 10–100 kDa, LIOP (300 mg/kg) had progressively increased their sensitivity to glucose (less insulin tolerance), reduced triglyceride levels, elevated the HDL/LDL ratio and decreased urinary albumin/creatinine ratio(ACR) compared to the control group. By pathological and immunohistochemical examinations, it was indicated that LIOP can restore the integrity of the glomerular capsules and increase the numbers of glomerular mesangial cells, associated with decreased expression of TGF-β on renal cortex in mice. Consistently, three days of LIOP (100 μg/mL) incubation also provided protection against STZ + AGEs-induced glucotoxicity in renal tubular cells (LLC-PK1), while the levels of NF-κB and TGF-β expression significantly decreased in a dose-dependent manner. Our findings demonstrate that LIOP treatment could ameliorate glucolipotoxicity-induced renal fibrosis, possibly partly via the inhibition of NF-κB/TGF-β1 signaling pathway in diabetic nephropathy mice.
Highlights
Diabetic mellitus (DM) is the most serious chronic disease in the world, and approximately 90% of diabetic patients belong to type 2 DM [1]
Hyperglycemia leads to elevation of oxidative stress, insulin resistance and pro-inflammatory cytokines, which are the key pathogeneses of renal damage in type 2 DM [3,4]
Our data showed that the glomerular TGF-β1 protein expression was significantly decreased in low molecular weight of Inonotus obliquus polysaccharides (IOP) fraction (LIOP) (1000 mg/kg) rather than RS (10 mg/kg) in diabetic nephropathy mice. These results strongly suggest the great potential of the LIOP as anti-fibrotic through the inhibition of transforming growth factor β (TGF-β) during chronic kidney disease
Summary
Diabetic mellitus (DM) is the most serious chronic disease in the world, and approximately 90% of diabetic patients belong to type 2 DM [1]. Ganoderma lucidum polysaccharides (GL-PS) were reported as potentially reducing serum glucose, creatinine (Cr), blood urea nitrogen (BUN), triglyceride (TG), urinary albumin excretion (UAE) and eventually improving the renal morphometric changes (glomerular size and mesangial matrix) on STZ-induced diabetic nephropathy in mice [19]. LIOP (100 μg/mL) incubation prevent STZ + AGEs-induced glucotoxicity in renal tubular cells (LLC-PK1) in a time-dependent manner (Figure 7). In our in vitro data, 72 h cell viability was significantly increased with LIOP (100 and 300 μg/mL) incubation in a dose-dependent manner, suggesting that LIOP treatment might prevent from STZ + AGEs-induced glucotoxicity in renal tubular cell (LLC-PK1). Our results further supported that a dramatic decrease in NF-κB (p65) and TGF-β expression was observed in the LIOP treatment in renal tubular cell (LLC-PK1) in a dose-dependent manner These results suggest that LIOP reduces renal fibrosis in diabetic nephropathy possibly through the NF-κB and TGF-β1 signaling pathways. The anti-glucolipotoxic and anti-nephrotoxic effects of LIOP accompanied by inhibition of NF-κB and TGF-β1 activation might be helpful mechanisms to reduce tubulointerstitial renal inflammation and fibrosis in diabetic nephropathy
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