Abstract
Background/Aims It is known that chronic low-grade inflammation contributes to the initiation and development of both diabetes and diabetic nephropathy (DN), so we designed this study to investigate the role of P2X7R and NLRP3 inflammasome in DN pathogenesis and the antagonistic effects of artificially cultivated Ophiocordyceps sinensis (ACOS). Methods A rat model of DN caused by high-fat-diet feeding and low-dose streptozotocin injection and a mouse podocyte injury model induced by high-glucose (HG) stimulation were established, and the intervention effects of ACOS on them were observed. The biological parameters of serum and urine and the pathological manifestations of kidney tissue were examined. The expression of mRNA and protein of P2X7R and NLRP3 inflammasome (NLRP3, ASC, and caspase-1) and downstream effectors (IL-1β and IL-18), as well as podocyte-associated molecules, was determined by real-time quantitative PCR and Western blot assay, respectively. Results The DN rats showed to have developed insulin resistance, elevated fasting blood glucose, increased urinary protein excretion, and serum creatinine level as well as corresponding glomerular pathological alterations including podocyte damages. ACOS significantly antagonized the above changes. The experiments in vivo and in vitro both displayed that the mRNA and protein expression of P2X7R, NLRP3, ASC, caspase1 (procaspase-1 mRNA in the gene level and active caspase-1 subunit P10 in the protein level), IL-1β, and IL-18 was significantly upregulated and the mRNA and protein expression of podocyte-associated molecules was significantly changed (downregulation of nephrin, podocin, and WT-1 expression and upregulation of desmin expression) indicating podocyte injury in the kidney tissue of DN rats and in the HG-stressed mouse podocytes, respectively. ACOS also significantly antagonized all the above changes. Conclusion Our research work suggests that P2X7R and NLRP3 inflammasome are involved in the pathogenesis of DN, and ACOS can effectively inhibit the high expression of P2X7R and the activation of NLRP3 inflammasome, which may contribute to the therapeutic effects of Ophiocordyceps sinensis.
Highlights
The global prevalence of diabetes has dramatically increased over the recent decades
The results showed that the mRNA and protein expression of purinergic 2X7 receptor (P2X7R), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), ASC, and caspase-1 was significantly upregulated in the Diabetic nephropathy (DN) group compared with the control group (P < 0 01), and the above expression was significantly downregulated in the HD-artificially cultivated Ophiocordyceps sinensis (ACOS) group compared with the DN group (P < 0 01) (Figure 4)
We successfully established a rat model of DN caused by type 2 DM, which was induced by highfat-diet feeding and low-dose streptozotocin injection and characterized by insulin resistance and hyperglycemia [25, 26]
Summary
The global prevalence of diabetes has dramatically increased over the recent decades. The International Diabetes Federation reported that the overall prevalence of diabetes was estimated to be 8.8% in people aged 20~79 years worldwide in 2015, which was predicted to rise to 10.4% in 2040 [1]. The China Noncommunicable Disease Surveillance Group reported that the overall prevalence of diabetes was estimated to be 11.6% and the prevalence of prediabetes in Chinese adult population aged 18 years or older was estimated to be 50.1% in 2010 [2]. Diabetes with its kidney complication, DN, has become a worldwide public health problem that seriously threatens human health
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