Chronic kidney disease (CKD) is a state of Klotho deficiency. The Klotho expression may be suppressed due to DNA hypermethylation in cancer cells so we have investigated the effects and possible mechanisms by which Klotho expression is regulated in human aortic smooth muscle cells (HASMCs). The vascular Klotho hypermethylation in radial arteries of patients with end-stage renal disease was described. Cultured HASMCs and 5/6-nephrectomized Sprague Dawley (SD) rats treated with indoxyl sulfate (IS) were used as in vitro and in vivo models, respectively. IS increased CpG hypermethylation of the Klotho gene and decreased Klotho expression in HASMCs, and potentiated HASMCs calcification. The expression of DNA methyltransferase (DNMT) 1 and 3a in HASMCs treated with IS was significantly increased and specific inhibition of DNA methyltransferase 1 by 5-aza-2'-deoxycytidine(5Aza-2dc) caused demethylation of the Klotho gene and increased Klotho expression. In rats, injection of IS potentiated vascular calcification, increased CpG hypermethylation of the Klotho gene and decreased Klotho expression in the aortic medial layer and all of these changes could be reverted by 5Aza-2dc treatment. Transcriptional suppression of vascular Klotho gene expression by IS and epigenetic modification of Klotho by IS may be an important pathological mechanism of vascular calcification in CKD.

Contrast-induced acute renal injury (CI-AKI) has become a common cause of hospital-acquired renal failure. However, the development of prophylaxis strategies and approved therapies for CI-AKI is limited. Salvianolic acid B (SB) can treat cardiovascular-related diseases. The aim of the present study was to assess the effect of SB on prevention of CI-AKI and explore its underlying mechanisms. We examined its effectiveness of preventing renal injury in a novel CI-AKI rat model. Compared with saline, intravenous SB pretreatment significantly attenuated elevations in serum creatinine and the histological changes of renal tubular injuries, reduced the number of apoptosis-positive tubular cells, activated Nrf2, and lowered the levels of renal oxidative stress induced by iodinated contrast media. The above renoprotection of SB was abolished by the PI3K inhibitor (wortmannin). In HK-2 cells, SB activated Nrf2 and decreased the levels of oxidative stress induced by hydrogen peroxide and subsequently improved cell viability. The above cytoprotection of SB was blocked by the PI3K inhibitor (wortmannin) or siNrf2. Thus, our results demonstrate that, due to its antioxidant properties, SB has the potential to effectively prevent CI-AKI via the PI3K/Akt/Nrf2 pathway.

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Renal fibrosis is associated with the reduction in the functional renal parenchyma and in most cases progresses to end-stage kidney failure, a devastating condition that requires lifelong dialysis or kidney transplantation. However, due to the extreme complexity in the pathogenesis of renal fibrosis and our limited knowledge, therapeutic options for renal fibrosis in the clinical setting are still scarce and often ineffective. Hence, further studies on the molecular mechanisms underlying renal fibrosis are compellingly needed. Multiple miRNAs have demonstrated to participate in kidney diseases in a TGF-β dependent or independent manner, but there is very little known about miR-155-5p on renal fibrosis. In the present study, we firstly explored the expression level and functions of miR-155-5p in the setting of renal fibrosis. Our research revealed that miR-155-5p is highly expressed in kidney tissues from patients and unilateral ureteral obstruction (UUO) rat models, and miR-155-5p knockdown significantly blocks renal fibrosis both in vivo and in vitro. In mechanism, our data demonstrate that miR-155-5p promotes renal fibrosis by increasing the phosphorylated activation of STAT3 via targeting SOCS1/6. Altogether, our findings highlight a miR-155-5p/SOCS/STAT3 axis in the pathogenesis of renal fibrosis, which may provide promising therapeutic targets for clinical prevention of this disease.

Aims: To investigate the impacts of combinatorial atorvastatin (Ator) perioperative administration and mesenchymal stem cell (MSC) implantation on therapeutic effects in the rat experimental acute kidney injury. Methods: The model of renal ischemia-reperfusion (I/R) injury was induced by the release of bilateral renal pedicle clamps following 45 min of occlusion. Immediately after reperfusion, CM-Dil-labeled MSCs (1 × 10⁶ cells) or vehicles only were administered through the carotid artery of the animals pretreated with or without Ator. Results: The combined treatment with Ator and MSCs (Ator+MSCs) markedly reduced the elevated levels of serum creatinine and blood urea nitrogen, as well as the severity of renal damage 24 h after I/R injury. In addition, we also observed inhibition of renal tubular cell apoptosis and promotion of proliferation in the Ator+MSCs group compared with the other groups. Consistent with the improvement in renal function and morphology, Ator pretreatment significantly ameliorated oxidative stress, inhibited inflammation response, and increased the viability of implanted MSCs. With regard to the further mechanism, we found that the expression of Toll-like receptor 4 (TLR4) and high-mobility group box 1, potential mediators of innate immunity, was significantly decreased in the Ator-treated groups. Conclusion: Ator treatment may protect the kidney undergoing I/R injury through suppression of TLR4 signaling, creating a better environment for the survival of grafted MSCs. The extra benefit of the Ator+MSCs combined therapy may result from the Ator-mediated inhibition of oxidative stress and inflammation in the ischemic kidney.

Contrast-induced acute kidney injury (CI-AKI) is a serious complication in patients after administration of iodinated contrast media. Proper animal models of CI-AKI can help understand the mechanisms involved and prevent the disorder. We used the 5/6-nephrectomized (NE) rat to develop a CI-AKI model and to evaluate differences in the toxic effects on the kidney between iohexol and iodixanol. We found that six weeks after ablative surgery was the preferred time to induce CI-AKI. We compared multiple pretreatment plans and found that dehydration for 48 hours before iodixanol (320, 10 mL/kg) administration was optimal to induce CI-AKI in the 5/6 NE rats. Compared with iodixanol, iohexol induced a significantly greater reduction in renal function, severe renal tissue damage, intrarenal hypoxia, and apoptotic tubular cells. Iohexol and iodixanol resulted in similarly marked increases in levels of inflammation and oxidative stress. In summary, the 5/6 NE rat combined with dehydration for 48 hours is a useful pretreatment to establish a novel and reliable CI-AKI model. Iohexol induced more severe CI-AKI than iodixanol in this model.

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