Arterial stiffness is an independent risk factor for stroke and myocardial infarction. This study was designed to investigate the role of SIRT1, an important deacetylase, and its relationship with Klotho, a kidney-derived aging-suppressor protein, in the pathogenesis of arterial stiffness and hypertension. We found that the serum level of Klotho was decreased by nearly 45% in patients with arterial stiffness and hypertension. Interestingly, Klotho haplodeficiency caused arterial stiffening and hypertension, as evidenced by significant increases in pulse wave velocity (PWV) and blood pressure (BP) in Klotho-haplodeficient (KL+/−) mice. Notably, the expression and activity of SIRT1 were decreased significantly in aortic endothelial and smooth muscle cells in KL+/− mice, suggesting that Klotho deficiency downregulates SIRT1. Treatment with SRT1720 (15 mg/kg/day, IP), a specific SIRT1 activator, abolished Klotho deficiency-induced arterial stiffness and hypertension in KL+/− mice. Klotho deficiency was associated with significant decreases in activities of AMP-activated protein kinase alpha (AMPKα) and endothelial nitric oxide synthase (eNOS) in aortas, which were abolished by SRT1720. Furthermore, Klotho deficiency upregulated NADPH oxidase activity and superoxide production, increased collagen expression, and enhanced elastin fragmentation in the media of aortas. These Klotho deficiency-associated changes were blocked by SRT1720. In conclusion, this study provides the first evidence that Klotho deficiency downregulates SIRT1 activity in arterial endothelial and smooth muscle cells. Pharmacological activation of SIRT1 may be an effective therapeutic strategy for arterial stiffness and hypertension.

Objective Klotho is an aging-suppressor gene which leads to accelerated aging when disrupted. This study was designed to investigate whether glutathione reductase (GR), a critical intracellular antioxidant enzyme, is involved in the pathogenesis of kidney damages associated with accelerated aging in Klotho-haplodeficient ( KL +/– ) mice. Methods and results Klotho-haplodeficient ( KL +/– ) mice and WT mice were used. We found that Klotho haplodeficiency impaired kidney function as evidenced by significant increases in plasma urea and creatinine and a decrease in urinary creatinine in KL +/– mice. The expression and activity of GR was decreased significantly in renal tubular epithelial cells of KL +/– mice, suggesting that Klotho deficiency downregulated GR. We constructed adeno-associated virus 2 (AAV2) carrying GR full-length cDNA (AAV-GR). Interestingly, in vivo AAV-GR delivery significantly improved Klotho deficiency-induced renal functional impairment and structural remodeling. Furthermore, in vivo expression of GR rescued the downregulation of the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, which subsequently diminished oxidative damages in kidneys, as evidenced by significant decreases in renal 4-HNE expression and urinary 8-isoprostane levels in KL mice. Conclusion This study provides the first evidence that Klotho deficiency-induced kidney damage may be partly attributed to downregulation of GR expression. In vivo delivery of AAV-GR may be a promising therapeutic approach for aging-related kidney damage.

Galectin-3 and myeloperoxidase (MPO) are novel biomarkers in the field of cardio-oncology, but conflicting results have been reported. Hence, a meta-analysis was performed to assess the monitoring value of galectin-3 and MPO in cancer-therapy-related cardiotoxicity. PubMed, Cochrane, Web of Science, Embase, CNKI databases and ClinicalTrials.gov were queried. According to the predefined inclusion and exclusion criteria, eight studies with 1979 patients were included in this meta-analysis. The examination of the study’s heterogeneity (I2), quality assessment and statistical analysis were performed by two reviewers. No significant differences in galectin-3 levels were noted before and after treatment (WMD = −0.10, 90% CI −6.06–5.85, I2: 99%), and a weaker relationship was observed between galectin-3 evaluations and cancer-therapy-related cardiotoxicity (HR = 1.39, 90% CI 0.97–1.98, I2: 0%). However, MPO levels were increased in patients post-treatment (SMD = 0.58, 90% CI 0.35–0.80, I2: 56%), and an increased risk of cardiotoxicity was associated with early pre–post MPO assessments (HR = 1.16, 90% CI 1.02–1.32, I2: 21%). Surprisingly, the MPO levels were a more effective indicator of the response to tumor treatment compared with the TnI (SMD = 2.46, 90% CI −0.26–5.19, I2: 96%) and NT-proBNP levels (SMD = 1.08, 90% CI −0.82–2.98, I2: 96%). In conclusion, our meta-analysis suggests that MPO may rep-resent a potential biomarker for the early detection of cardiotoxicity in current cardio-oncology practice, but the monitoring value of galectin-3 requires further study.

Background This study focused on renal arteriosclerosis and aimed to explore the relationship between Klotho and SIRT1 by morphological staining, which will help to provide new ideas for the treatment of renal-aging-related diseases and a theoretical basis for the development of new drugs. Methods Kidney tissue samples were collected from patients who underwent nephrectomy. HK-2 cells were cultured. The Hematoxylin-eosin (HE) staining, Periodic Acid-Schiff (PAS) staining, Masson’s Trichrome staining, Immunohistochemistry (IHC) staining, Immunofluorescence (ICC) and bioinformatics means were used for this study. Results HE staining showed that glomerulosclerosis was atrophic and cast was significantly increased luminal narrowing of renal arterioles in aging group. PAS staining showed that the number of podocytes was reduced, the mesangial matrix expansion and the intimal fibrosis of renal arterioles. Masson’s trichrome staining showed that there was massive collagen proliferation in the tubulointerstitial in aging group, as well as intimal thickening and fibrin deposition in the tubular walls of arterioles. IHC staining showed that the expression of Klotho and SIRT1 protein was downregulated in aging group and the trend of the two was positively correlated (P < 0.01). Klotho and SIRT1 co-localized in HK-2 cells and kidney tissue. The GEPIA database analysis showed a significant positive correlation between Klotho and SIRT1 in multiple human tissues and tumors. Conclusion Glomerulosclerosis in aging group is accompanied by low expression of Klotho and SIRT1 in renal tissue, and Klotho is positively correlated with SIRT1. Klotho-SIRT1 pathway may be involved in the occurrence and development of renal-aging-related diseases.