Accumulating evidence reveals that both inflammation and lymphocyte dysfunction play a vital role in the development of diabetic nephropathy (DN). Hyperoside (HPS) or quercetin-3-O-galactoside is an active flavonoid glycoside mainly found in the Chinese herbal medicine Tu-Si-Zi. Although HPS has a variety of pharmacological effects, including anti-oxidative and anti-apoptotic activities as well as podocyte-protective effects, its underlying anti-inflammatory mechanisms remain unclear. Herein, we investigated the therapeutic effects of HPS on murine DN and the potential mechanisms responsible for its efficacy. We used C57BLKS/6J ^Lepdb/db mice and a high glucose (HG)-induced bone marrow-derived macrophage (BMDM) polarization system to investigate the potentially protective effects of HPS on DN. Our results showed that HPS markedly reduced diabetes-induced albuminuria and glomerular mesangial matrix expansion, accompanied with a significant improvement of fasting blood glucose level, hyperlipidaemia and body weight. Mechanistically, pretreatment with HPS effectively regulated macrophage polarization by shifting proinflammatory M1 macrophages (F4/80⁺CD11b⁺CD86⁺) to anti-inflammatory M2 ones (F4/80⁺CD11b⁺CD206⁺) in vivo and in bone marrow-derived macrophages (BMDMs) in vitro, resulting in the inhibition of renal proinflammatory macrophage infiltration and the reduction in expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) while increasing expression of anti-inflammatory cytokine Arg-1 and CD163/CD206 surface molecules. Unexpectedly, pretreatment with HPS suppressed CD4⁺ T cell proliferation in a coculture model of IL-4-induced M2 macrophages and splenic CD4⁺ T cells while promoting their differentiation into CD4⁺IL-4⁺ Th2 and CD4⁺Foxp3⁺ Treg cells. Taken together, we demonstrate that HPS ameliorates murine DN via promoting macrophage polarization from an M1 to M2 phenotype and CD4⁺ T cell differentiation into Th2 and Treg populations. Our findings may be implicated for the treatment of DN in clinic.

Objective: Diabetic kidney disease (DKD) has become the major cause of end-stage renal disease (ESRD) associated with the progression of renal fibrosis. As gut microbiota dysbiosis is closely related to renal damage and fibrosis, we investigated the role of gut microbiota and microbiota-related serum metabolites in DKD progression in this study.Methods: Fecal and serum samples obtained from predialysis DKD patients from January 2017 to December 2019 were detected using 16S rRNA gene sequencing and liquid chromatography-mass spectrometry, respectively. Forty-one predialysis patients were divided into two groups according to their estimated glomerular filtration rate (eGFR): the DKD non-ESRD group (eGFR ≥ 15 ml/min/1.73 m²) (n = 22), and the DKD ESRD group (eGFR < 15 ml/min/1.73 m²) (n = 19). The metabolic pathways related to differential serum metabolites were obtained by the KEGG pathway analysis. Differences between the two groups relative to gut microbiota profiles and serum metabolites were investigated, and associations between gut microbiota and metabolite concentrations were assessed. Correlations between clinical indicators and both microbiota-related metabolites and gut microbiota were calculated by Spearman rank correlation coefficient and visualized by heatmap.Results: Eleven different intestinal floras and 239 different serum metabolites were identified between the two groups. Of 239 serum metabolites, 192 related to the 11 different intestinal flora were mainly enriched in six metabolic pathways, among which, phenylalanine and tryptophan metabolic pathways were most associated with DKD progression. Four microbiota-related metabolites in the phenylalanine metabolic pathway [hippuric acid (HA), L-(−)-3-phenylactic acid, trans-3-hydroxy-cinnamate, and dihydro-3-coumaric acid] and indole-3 acetic acid (IAA) in the tryptophan metabolic pathway positively correlated with DKD progression, whereas L-tryptophan in the tryptophan metabolic pathway had a negative correlation. Intestinal flora g_Abiotrophia and g_norank_f_Peptococcaceae were positively correlated with the increase in renal function indicators and serum metabolite HA. G_Lachnospiraceae_NC2004_Group was negatively correlated with the increase in renal function indicators and serum metabolites [L-(−)-3-phenyllactic acid and IAA].Conclusions: This study highlights the interaction among gut microbiota, serum metabolites, and clinical indicators in predialysis DKD patients, and provides new insights into the role of gut microbiota and microbiota-related serum metabolites that were enriched in the phenylalanine and tryptophan metabolic pathways, which correlated with the progression of DKD.

Introduction: Renal podocyte injury, apoptosis and autophagy are involved in the occurrence and development of diabetic nephropathy (DN). Kaempferol (KPF) has the promotion of autophagy and inhibition of apoptosis properties in the development of miscellaneous diseases, but these functions in DN have not yet been elucidated.Methods: We used db/db mice to evaluate the protective role of KPF on DN. The anti-DN effect of KPF was evaluated by urine albumin-to-creatinine ratio and pathological changes of kidney tissue. Injury of podocytes was observed through Transmission electron microscopy. Immunofluorescence, Western blot, and Immunohistochemistry were used to detect the protein expression of podocyte-associated molecules, autophagy, and AMPK/mTOR pathway.Results: We demonstrated that KPF treatment significantly attenuated diabetes-induced albuminuria and glycolipid metabolism dysfunction. In addition, KPF alleviated mesangial matrix expansion, glomerular basement membrane thickening and loss or fusion of podocytes. Mechanistically, KPF treatment regulated the expression of autophagic proteins (upregulated LC3II, Beclin-1, Atg7 and Atg 5, and downregulated p62/SQSTM1), accompanied by inhibited renal apoptosis (downregulated Caspase 3 and Bax, and upregulated Bcl-2). KPF could significantly regulate the AMPK/mTOR signaling pathways by increasing p-AMPK and decreasing p-mTOR expressions.Discussion: In conclusion, KPF might have a protective effect on DN through reduced apoptosis and enhanced podocytes autophagy, which were correlated with regulating AMPK/mTOR pathways.

Background: Diabetes ranks among the most widespread diseases globally, with the kidneys being particularly susceptible to its vascular complications. The identification of proteins for pathogenesis and novel drug targets remains imperative. This study aims to investigate roles of circulating inflammatory proteins in diabetic renal complications.Methods: Data on the proteins were derived from a genome-wide protein quantitative trait locus (pQTL) study, while data on diabetic renal complications came from the FinnGen study. In this study, proteome-wide Mendelian randomization (MR) and colocalization analyses were used to assess the relationship between circulating inflammatory proteins and diabetic renal complications.Results: MR approach indicated that elevated levels of interleukin 12B (IL-12B) (OR 1.691, 95%CI 1.179–2.427, P=4.34×10^-3) and LIF interleukin 6 family cytokine (LIF) (OR 1.349, 95%CI 1.010–1.801, P=4.23×10^-2) increased the risk of type 1 diabetes (T1D) with renal complications, while higher levels of fibroblast growth factor 19 (FGF19) (OR 1.202, 95%CI 1.009–1.432, P=3.93×10^-2), fibroblast growth factor 23 (FGF23) (OR 1.379, 95%CI 1.035–1.837, P=2.82×10^-2), C-C motif chemokine ligand 7 (CCL7) (OR 1.385, 95%CI 1.111–1.725, P=3.76×10^-3), and TNF superfamily member 14 (TNFSF14) (OR 1.244, 95%CI 1.066–1.451, P=5.63×10^-3) indicated potential risk factors for type 2 diabetes (T2D) with renal complications. Colocalization analysis supported these findings, revealing that most identified proteins, except for DNER, likely share causal variants with diabetic renal complications.Conclusion: Our study established associations between specific circulating inflammatory proteins and the risk of diabetic renal complications, suggesting these proteins as targets for further investigation into the pathogenesis and potential therapeutic interventions for T1D and T2D with renal complications.

Background: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, and current pharmacotherapies provide limited renal protection. Qitu Qushi Formula (QTQSF), a traditional Chinese medicine prescription, has shown therapeutic potential in DKD, but its underlying mechanisms remain unclear. This study aimed to elucidate whether QTQSF alleviates DKD via gut microbiota-mediated pathways. Methods: Clinical, animal, and cellular studies were integrated to investigate the therapeutic effects of QTQSF. Clinical samples from 30 patients with type 2 DKD received QTQSF treatment for 6 months was used to assess renal function and gut microbiota. To explore microbiota-mediated mechanisms, db/db mice, pseudo-germ-free models, and fecal microbiota transplantation (FMT) were utilized. Multi-omics analyses, including 16S rRNA sequencing, untargeted and targeted metabolomics, and transcriptomics, were conducted to uncover key pathways underlying QTQSF’s efficacy. Results: QTQSF significantly improved renal function and remodeled gut microbial composition in DKD patients. In db/db mice, QTQSF reduced albuminuria, fibrosis, and apoptosis, whereas these protective effects were attenuated after gut microbiota depletion. FMT supported that gut microbiota mediated the renoprotective effects of QTQSF. Integrated multi-omics analyses revealed that QTQSF enhanced microbial tryptophan metabolism and increased the gut microbiota-derived metabolite indole-3-propionic acid (IPA). Elevated IPA levels were associated with regulation of the renal Sirt1/FoxO1 pathway, which was further validated in podocytes as a key mechanism underlying the anti-apoptotic effects. Conclusion: QTQSF may ameliorate DKD by enhancing gut microbiota-derived IPA production and regulating the Sirt1/FoxO1 signaling pathway, thereby attenuating renal injury. These findings provide mechanistic insight into the renoprotective effects of QTQSF and highlight a gut microbiota–metabolite–host signaling axis in DKD.

Original Article The efficacy and safety of self-administered acupressure on respiratory tract infection in chronic kidney disease: a randomized controlled trial Meifang Liu, Hongqin Sheng, Jiahui Huang, Meiling Xuan, Wenwei Ouyang, Yanmei Zhang, Shuzhen Zhou, Lu Zeng, Lizhe Fu, Yin Chen, Xinyi Huang, Kaiqi Huang, Yifan Wu, Xusheng Liu, Lei Zhang