Scutellarin Ameliorates Renal Injury via Increasing CCN1 Expression and Suppressing NLRP3 Inflammasome Activation in Hyperuricemic Mice

Considerable evidences have indicated that elevated uric acid (UA) was involved in renal tubular injury leading to hyperuricemic nephropathy (HN). Scutellarin is a biologically active flavonoid derived from the Chinese traditional herb Erigeron breviscapus Hand-Mazz, which has been widely used in the treatment of cardiovascular and cerebrovascular diseases. In the present study, we analyzed the effect of scutellarin on HN, by using C57BL/6 mice and human renal tubular epithelial cell line HK-2 which was subjected to adenine/potassium oxonate and UA to mimic a HN injury. The HN mice showed a significant decrease in renal function with the increased SCr and blood urea nitrogen (BUN) (p < 0.05). Hematoxylin-eosin staining results showed a histological injury in HN mice kidney tissues with severe tubular damage. Scutellarin dose dependently alleviated the renal injury of the HN model (p < 0.05), and a dose of 20 mg/kg/day remarkably reduced the Scr level (26.10 +/- 3.23 mu mol/ml vs. 48.39 +/- 7.51 mu mol/ml, p < 0.05) and BUN (151.12 +/- 30.24 mmol/L vs. 210.43 +/- 45.67 mmol/L, p < 0.05) compared with the HN model group. Similarly, scutellarin decreased NGAL, Kim-1, cystatin C, and IL-18 protein expression levels in HN mouse (p < 0.05). Overexpressed CCN1 could not induce NLRP3 inflammasome activation, with no change of mRNA and protein expression levels of NLRP3, ASC, and pro-caspase-1 compared with the control HK-2. However, HK-2 showed a significant NLRP3 inflammasome activation and apoptosis. Importantly, knockdown of CCN1 not only aggravated NLRP3 inflammasome activation and apoptosis but also abrogated the protective effect of scutellarin in UA-induced HK-2 injury. Thus, scutellarin might alleviate HN progression via a mechanism involved in CCN1 regulation on NLRP3 inflammasome activation

Critical Role of Cysteine-Rich Protein 61 in Mediating the Activation of Renal Fibroblasts

ObjectiveTo explore the expression of cysteine-rich protein 61 (Cyr61) in ischemic renal fibrosis and the role of Cyr61 in mediating the activation of renal fibroblasts.Methods(1) The rat model of renal fibrosis was established after ischemia-reperfusion acute renal injury (IR-AKI). We detected the renal function by biochemical test, evaluated the fibrosis by Masson staining, and detected the expression of Cyr61 by western blotting. (2) Bioinformatics technique was adopted to analyze the expression of Cyr61 in activated renal fibroblasts. (3) Normal rat kidney fibroblast cells (NRK-49F cells) with over-expression of Cyr61 (Cyr61+) and low-expression of it (Cyr61--) were established by plasmid transfection. Then part of the cells were activated by TGF-β1 and NRK-49F cells were divided into control group, activated group, Cyr61+/Cyr61-- group and Cyr61+/Cyr61-- activated group. The expression of Cyr61 and fibrosis related factors (Col1α1, Col3α1, MMP9, and MMP13) were ascertained by PCR and western blotting. Cell proliferation was discovered by CCK8 method, cell cycle was analyzed by flow cytometry, and the transcription of cell senescence related factors (P53, P21, Rb, and P16) were ascertained by PCR method.Results(1) In the process of fibrosis after IR-AKI, the area of collagen fiber was most obviously at AKI 1W, while the Cyr61 protein was at the lowest level at AKI 1W. (2) Gene chip analysis showed that the expression of Cyr61 was decreased in renal fibroblasts after IR. (3) Compared with control group, Cyr61+ group expressed less Col1α1 or Col3α1, as well as more MMP9 and MMP13. At the same time, the proliferation of Cyr61+ group decreased and cells in G1 phases increased with more transcription of P53, P21, and Rb (all P &lt; 0.05). Compared with activated group, the results of Cyr61+ activated group were similar to the above. The above effects of low expression group were just the opposite. In addition, there was no difference in the transcription of P16 among these groups (P &gt; 0.05).ConclusionCyr61 may not only inhibit the fibrotic phenotype of fibroblasts, but may also inhibit proliferation by promoting fibroblasts arrest in G1 phase through the P53/P21/Rb interrelated cell senescence pathway, subsequently affecting the process of ischemic renal fibrosis

Effects of uric acid-lowering therapy on the progression of chronic kidney disease: a systematic review and meta-analysis

Objectives: Whether uric acid levels were associated with the progression of chronic kidney disease (CKD) remained controversial. This meta-analysis was aimed to assess the effect of lowering serum uric acid therapy on the progression of CKD to clarify the role of uric acid in the progression of CKD indirectly. Methods: Pubmed, Embase, the Cochrane library, CBM were searched for randomized controlled trials (RCTs) that assessed the efficiency of lowering serum uric acid therapy on the progression of CKD without language restriction. Summary estimates of weighted mean differences (WMDs) and relative risk (RR) were obtained by using random-effect or fixed-effect models. Sensitivity analyses were performed to identify the source of heterogeneity. Results: A total of 12 randomized controlled trials with 832 CKD participants were included in the analysis. Pooled estimate for eGFR was in favor of lowering serum uric acid therapy with a mean difference (MD) of 3.88 ml/min/1.73 m2, 95% CI 1.26–6.49 ml/min/1.73 m2, p = .004 and this was consistent with results for serum creatinine. The risk of worsening of kidney function or ESRD or death was significantly decreased in the treatment group compared to the control group (RR 0.39, 95% CI 0.28–0.52, p< .01). Conclusions: Uric acid-lowering therapy may be effective in retarding the progression of CKD. Further randomized controlled trials should be performed to confirm the effect of lowering serum uric acid therapy on the progression of CKD

Mesenchymal stem cells protect against sepsis-associated acute kidney injury by inducing Gal-9/Tim-3 to remodel immune homeostasis

AbstractObjective The present study investigated the specific mechanism by which mesenchymal stem cells (MSCs) protect against sepsis-associated acute kidney injury (SA-AKI).Methods Male C57BL/6 mice underwent cecal ligation and puncture surgery to induce sepsis and then received either normal IgG or MSCs (1 × 106 cells, intravenously) plus Gal-9 or soluble Tim-3 3 h after surgery.Results After cecal ligation and puncture surgery, the mice injected with Gal-9 or MSCs plus Gal-9 had a higher survival rate than the mice in the IgG treatment group. Treatment with MSCs plus Gal-9 decreased serum creatinine and blood urea nitrogen levels, improved tubular function recovery, reduced IL-17 and RORγt levels and induced IL-10 and FOXP3 expression. Additionally, the Th17/Treg cell balance was altered. However, when soluble Tim-3 was used to block the Gal-9/Tim-3 pathway, the septic mice developed kidney injury and exhibited increased mortality. Treatment with MSCs plus soluble Tim-3 blunted the therapeutic effect of MSCs, inhibited the induction of Tregs, and suppressed the inhibition of differentiation into Th17 cells.Conclusion Treatment with MSCs significantly reversed the Th1/Th2 balance. Thus, the Gal-9/Tim-3 pathway may be an important mechanism of MSC-mediated protection against SA-AKI

Effects of uric acid-lowering therapy on the progression of chronic kidney disease: a systematic review and meta-analysis

<p><b>Objectives:</b> Whether uric acid levels were associated with the progression of chronic kidney disease (CKD) remained controversial. This meta-analysis was aimed to assess the effect of lowering serum uric acid therapy on the progression of CKD to clarify the role of uric acid in the progression of CKD indirectly.</p> <p><b>Methods:</b> Pubmed, Embase, the Cochrane library, CBM were searched for randomized controlled trials (RCTs) that assessed the efficiency of lowering serum uric acid therapy on the progression of CKD without language restriction. Summary estimates of weighted mean differences (WMDs) and relative risk (RR) were obtained by using random-effect or fixed-effect models. Sensitivity analyses were performed to identify the source of heterogeneity.</p> <p><b>Results:</b> A total of 12 randomized controlled trials with 832 CKD participants were included in the analysis. Pooled estimate for eGFR was in favor of lowering serum uric acid therapy with a mean difference (MD) of 3.88 ml/min/1.73 m², 95% CI 1.26–6.49 ml/min/1.73 m², <i>p</i> = .004 and this was consistent with results for serum creatinine. The risk of worsening of kidney function or ESRD or death was significantly decreased in the treatment group compared to the control group (RR 0.39, 95% CI 0.28–0.52, <i>p</i>< .01).</p> <p><b>Conclusions:</b> Uric acid-lowering therapy may be effective in retarding the progression of CKD. Further randomized controlled trials should be performed to confirm the effect of lowering serum uric acid therapy on the progression of CKD.</p

Simultaneous Electrochemical Detection of Cd²⁺ and Pb²⁺ Based on an MOF-Derived Carbon Composite Linked with Multiwalled Carbon Nanotubes

Heavy metal ion (HMI) pollution is a serious threat to human health and the ecosystem. Therefore, there is an urgent need to develop a fast and sensitive platform for heavy metal ion detection. In this work, a novel sensing platform based on ZIF-67-derived cobalt/nitrogen-doped carbon (NC) composite polyhedrons linked with multiwalled carbon nanotubes (MWCNTs), termed Co@NC/MWCNT, for the simultaneous monitoring of Cd2+ and Pb2+ was established. In detail, nanoporous ZIF-67 was first in situ grown on the MWCNTs, followed by carbonization, endowing the composite with good electrical conductivity and a large specific surface area, providing more active sites for subsequent metal ion attachment. Under optimal parameters, the proposed sensing platform exhibited a relatively wider linear range of 0.12–2.5 μM, with lower limits of detection (LODs) of 4.5 nM (Cd2+) and 4.9 nM (Pb2+). Notably, it was worth mentioning that the linearity of the as-prepared sensing platform in the actual water sample was highly consistent with the linearity in the buffer solution, showing outstanding anti-interference performance. Finally, the designed sensing platform performed well in several kinds of natural water environment when compared with the standard method, demonstrating huge potential in trace HMI monitoring

Hexarelin alleviates apoptosis on ischemic acute kidney injury via MDM2/p53 pathway

Abstract Introduction Hexarelin exhibits significant protection against organ injury in models of ischemia/reperfusion (I/R)-induced injury (IRI). Nevertheless, the impact of Hexarelin on acute kidney injury (AKI) and its underlying mechanism remains unclear. In this study, we investigated the therapeutic potential of Hexarelin in I/R-induced AKI and elucidated its molecular mechanisms. Methods We assessed the protective effects of Hexarelin through both in vivo and in vitro experiments. In the I/R-induced AKI model, rats were pretreated with Hexarelin at 100 μg/kg/d for 7 days before being sacrificed 24 h post-IRI. Subsequently, kidney function, histology, and apoptosis were assessed. In vitro, hypoxia/reoxygenation (H/R)-induced HK-2 cell model was used to investigate the impact of Hexarelin on apoptosis in HK-2 cells. Then, we employed molecular docking using a pharmmapper server and autodock software to identify potential target proteins of Hexarelin. Results In this study, rats subjected to I/R developed severe kidney injury characterized by tubular necrosis, tubular dilatation, increased serum creatinine levels, and cell apoptosis. However, pretreatment with Hexarelin exhibited a protective effect by mitigating post-ischemic kidney pathological changes, improving renal function, and inhibiting apoptosis. This was achieved through the downregulation of conventional apoptosis-related genes, such as Caspase-3, Bax and Bad, and the upregulation of the anti-apoptotic protein Bcl-2. Consistent with the in vivo results, Hexarelin also reduced cell apoptosis in post-H/R HK-2 cells. Furthermore, our analysis using GSEA confirmed the essential role of the apoptosis pathway in I/R-induced AKI. Molecular docking revealed a strong binding affinity between Hexarelin and MDM2, suggesting the potential mechanism of Hexarelin’s anti-apoptosis effect at least partially through its interaction with MDM2, a well-known negative regulator of apoptosis-related protein that of p53. To validate these findings, we evaluated the relative expression of MDM2 and p53 in I/R-induced AKI with or without Hexarelin pre-administration and observed a significant suppression of MDM2 and p53 by Hexarelin in both in vivo and in vitro experiments. Conclusion Collectively, Hexarelin was identified as a promising medication in protecting apoptosis against I/R-induced AKI