sinomenine and Kidney-Diseases

This study attempts to investigate the therapeutic effect of sinomenine on renal fibrosis and its mechanism.. The 8-week-old C57BL/6 male mice were randomly divided into sham group, UUO model group, UUO sinomenine group (UUO + Sino 50), UUO + sinomenine group (UUO + Sino 100), UUO + exosome group (exo), and UUO + exo-inhibitor. The pathological changes of kidney were observed by H&E staining, the degree of renal interstitial fibrosis was detected by MASSON and Sirius red staining, and the expressions of fibrosis and autophagy markers were detected by real-time fluorescence quantitative PCR and WB. NTA and electron microscopy were used to analyze exo secretion after sinomenine treatment.. Sinomenine could improve the progression of renal fibrosis without causing tissue damage including heart, lungs and liver. Sinomenine could promote autophagosome formation. It could promote the secretion of exosomes from bone marrow mesenchymal stem cells (BMSCs). Sinomine regulates the PI3K-AKT pathway through BMSC-exo carrying miR-204-5p, affecting autophagy level and alleviating the process of renal fibrosis.. Our study suggests that sinomine could improve the progression of renal fibrosis by influencing the expression of miR-204-5p in BMSC-exo and regulating the PI3K-AKT pathway.

Topics: Animals; Autophagy; Exosomes; Fibrosis; Kidney Diseases; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; MicroRNAs; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt

Renal fibrosis is the common feature of chronic kidney disease and mainly mediated by TGFβ-associated pro-fibrogenic signaling, which causes excessive extracellular matrix accumulation and successive loss of kidney functions. Sinomenine (SIN), an alkaloid derived from medicinal herb extensively used in treatment of rheumatoid arthritis and various inflammatory disorders, displays renal protective properties in experimental animals; however its pharmacological potency against renal fibrosis is not explored. In this study we report that SIN possesses strong anti-renal fibrosis functions in kidney cell and in mouse fibrotic kidney. SIN beneficially modulated the pro-fibrogenic protein expression in TGFβ-treated kidney cells and attenuated the renal fibrotic pathogenesis incurred by unilateral ureteral obstruction (UUO), which correlated with its activation of Nrf2 signaling - the key defender against oxidative stress with anti-fibrotic potentials. Further investigation on its regulation of Nrf2 downstream events revealed that SIN significantly balanced oxidative stress via improving the expression and activity of anti-oxidant and detoxifying enzymes, and interrupted the pro-fibrogenic signaling of TGFβ/Smad and Wnt/β-catenin. Even more impressively SIN achieved its anti-fibrotic activities in an Nrf2-dependent manner, suggesting that SIN regulation of Nrf2-associated anti-fibrotic activities constitutes a critical component of SIN's renoprotective functions. Collectively our studies have demonstrated a novel anti-fibrotic property of SIN and its upstream events and provided a molecular basis for SIN's potential applications in treatment of renal fibrosis-associated kidney disorders.

Topics: Animals; Antirheumatic Agents; Catalase; Fibrosis; Glutathione Peroxidase; HEK293 Cells; Humans; Kidney Diseases; Mice; Morphinans; NF-E2-Related Factor 2; Oxidative Stress; Signal Transduction; Superoxide Dismutase; Transforming Growth Factor beta1