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Schisandrin C attenuates renal damage in diabetic nephropathy by regulating macrophage polarization.

ABSTRACT: This study aimed to investigate the protective effects of Schisandrin C during diabetic nephropathy (DN) treatment. After DN induction, mice were treated with Schisandrin C, and diabetic metabolic parameters and renal function-associated factors were measured. Renal structural damage was evaluated by hematoxylin and eosin (HE) and Masson's trichrome staining. Macrophage polarization and macrophage-mediated inflammatory factors were detected in the kidneys by immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA), respectively. The Swiprosin-1/interferon (IFN)-?-R? pathway was evaluated by western blot (WB) analysis. The preliminary effects of Schisandrin C in high-glucose-stimulated macrophages from DN mice were verified by flow cytometry, ELISA, and WB analyses. These results indicated that Schisandrin C significantly regulated physiological parameters in DN. Renal structural damage was mitigated by Schisandrin C. In Schisandrin-C-treated groups, the expression levels of CD86, tumor necrosis factor (TNF)-?, interleukin (IL)-6, and IL-1? decreased, whereas CD206, IL-10, and transforming growth factor (TGF)-? expression levels increased. In vitro experiments indicated that among CD86⁺ cells, TNF-?, IL-6, and IL-1? expression levels significantly decreased, whereas among CD206⁺ cells, IL-10 and TGF-? expression increased following Schisandrin-C-treatment. Finally, Schisandrin C inhibited the expression of Swiprosin-1, IFN-?-R?, phospho-Janus kinase 2 (p-JAK2), phospho-signal transducer and activator of transcription 1 (p-STAT1), and p-STAT3, in both DN model mice and high-glucose-stimulated RAW264.7 cells. The present study indicated a novel use for Schisandrin C to suppress DN progression, by promoting M1 to M2 macrophage polarization. Schisandrin C exerted protective effects against DN by regulating the polarization-dependent Swiprosin-1/IFN-?-R? signaling pathway in macrophages.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7847524 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Schisandrin C attenuates renal damage in diabetic nephropathy by regulating macrophage polarization.

Wang Yu Y Cui Jingqiu J Liu Ming M Shao Yingqi Y Dong Xiaoying X

American journal of translational research 20210115 1

This study aimed to investigate the protective effects of Schisandrin C during diabetic nephropathy (DN) treatment. After DN induction, mice were treated with Schisandrin C, and diabetic metabolic parameters and renal function-associated factors were measured. Renal structural damage was evaluated by hematoxylin and eosin (HE) and Masson's trichrome staining. Macrophage polarization and macrophage-mediated inflammatory factors were detected in the kidneys by immunohistochemistry (IHC) and enzyme ...[more]

PMID: 33527019

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Project description:BackgroundChronic kidney disease often leads to kidney dysfunction due to renal fibrosis, regardless of the initial cause of kidney damage. Macrophages are crucial players in the progression of renal fibrosis as they stimulate inflammation, activate fibroblasts, and contribute to extracellular matrix deposition, influenced by their metabolic state. Nucleotide-binding domain and LRR-containing protein X (NLRX1) is an innate immune receptor independent of inflammasomes and is found in mitochondria, and it plays a role in immune responses and cell metabolism. The specific impact of NLRX1 on macrophages and its involvement in renal fibrosis is not fully understood.MethodsTo explore the specific role of NLRX1 in macrophages, bone-marrow-derived macrophages (BMDMs) extracted from wild-type (WT) and NLRX1 knockout (KO) mice were stimulated with pro-inflammatory and pro-fibrotic factors to induce M1 and M2 polarization in vitro. The expression levels of macrophage polarization markers (Nos2, Mgl1, Arg1, and Mrc1), as well as the secretion of transforming growth factor β (TGFβ), were measured using RT-PCR and ELISA. Seahorse-based bioenergetics analysis was used to assess mitochondrial respiration in naïve and polarized BMDMs obtained from WT and NLRX1 KO mice. In vivo, WT and NLRX1 KO mice were subjected to unilateral ureter obstruction (UUO) surgery to induce renal fibrosis. Kidney injury, macrophage phenotypic profile, and fibrosis markers were assessed using RT-PCR. Histological staining (PASD and Sirius red) was used to quantify kidney injury and fibrosis.ResultsCompared to the WT group, an increased gene expression of M2 markers-including Mgl1 and Mrc1-and enhanced TGFβ secretion were found in naïve BMDMs extracted from NLRX1 KO mice, indicating functional polarization towards the pro-fibrotic M2 subtype. NLRX1 KO naïve macrophages also showed a significantly enhanced oxygen consumption rate compared to WT cells and increased basal respiration and maximal respiration capacities that equal the level of M2-polarized macrophages. In vivo, we found that NLRX1 KO mice presented enhanced M2 polarization markers together with enhanced tubular injury and fibrosis demonstrated by augmented TGFβ levels, fibronectin, and collagen accumulation.ConclusionsOur findings highlight the unique role of NLRX1 in regulating the metabolism and function of macrophages, ultimately protecting against excessive renal injury and fibrosis in UUO.

Project description:Diabetic nephropathy (DN) is one of the major complications of diabetes and contributes significantly towards end-stage renal disease. Previous studies have identified the gene encoding carnosinase (CN-1) as a predisposing factor for DN. Despite this fact, the relationship of the level of serum CN-1 and the progression of DN remains uninvestigated. Thus, the proposed study focused on clarifying the relationship among serum CN-1, indicators of renal function and tissue injury, and the progression of DN. A total of 14 patients with minimal changes disease (MCD) and 37 patients with DN were enrolled in the study. Additionally, 20 healthy volunteers were recruited as control. Further, DN patients were classified according to urinary albumin excretion rate into two groups: DN with microalbuminuria (n = 11) and DN with macroalbuminuria (n = 26). Clinical indicators including urinary protein components, serum carnosine concentration, serum CN-1 concentration and activity, and renal biopsy tissue injury indexes were included for analyzation. The serum CN-1 concentration and activity were observed to be the highest, but the serum carnosine concentration was the lowest in DN macroalbuminuria group. Moreover, within DN group, the concentration of serum CN-1 was positively correlated with uric acid (UA, r = 0.376, p = 0.026) and serum creatinine (SCr, r = 0.399, p = 0.018) and negatively correlated with serum albumin (Alb, r = - 0.348, p = 0.041) and estimated glomerular filtration rate (eGRF, r = - 0.432, p = 0.010). Furthermore, the concentration of serum CN-1 was discovered to be positively correlated with indicators including 24-h urinary protein-creatinine ratio (24 h-U-PRO/CRE, r = 0.528, p = 0.001), urinary albumin-to-creatinine ratio (Alb/CRE, r = 0.671, p = 0.000), urinary transferrin (TRF, r = 0.658, p = 0.000), retinol-binding protein (RBP, r = 0.523, p = 0.001), N-acetyl-glycosaminidase (NAG, r = 0.381, p = 0.024), immunoglobulin G (IgG, r = 0.522, p = 0.001), cystatin C (Cys-C, r = 0.539, p = 0.001), beta-2-microglobulin (β2-MG, r = 0.437, p = 0.009), and alpha-1-macroglobulin (α1-MG, r = 0.480, p = 0.004). Besides, in DN with macroalbuminuria group, serum CN-1 also showed a positive correlation with indicators of fibrosis, oxidative stress, and renal tubular injury. Taken together, our data suggested that the level of CN-1 was increased as clinical DN progressed. Thus, the level of serum CN-1 might be an important character during the occurrence and progression of DN. Our study will contribute significantly to future studies focused on dissecting the underlying mechanism of DN.

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Schisandrin C attenuates renal damage in diabetic nephropathy by regulating macrophage polarization.

Publications

Schisandrin C attenuates renal damage in diabetic nephropathy by regulating macrophage polarization.

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