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Mesenchymal stem cells (MSCs) have attracted a great deal of interest as a therapeutic tool for renal fibrosis. Although both adipose-derived and bone marrow-derived MSCs (ADSCs and BMSCs, respectively) suppress renal fibrosis, which of these two has a stronger therapeutic effect remains unclear. This study aimed to compare the antifibrotic effects of ADSCs and BMSCs extracted from adipose tissue and bone marrow derived from the same rats. When cultured in serum-containing medium, ADSCs had a more potent inhibitory effect than BMSCs on renal fibrosis induced by ischemia-reperfusion injury in rats. ADSCs and BMSCs cultured in serum-free medium were equally effective in suppressing renal fibrosis. Mice infused with ADSCs (serum-containing or serum-free cultivation) had a higher death rate from pulmonary embolism than those infused with BMSCs. In vitro, mRNA levels of tissue factor, tumor necrosis factor-α-induced protein 6 and prostaglandin E synthase were higher in ADSCs than in BMSCs, while that of vascular endothelial growth factor was higher in BMSCs than in ADSCs. Although ADSCs had a stronger antifibrotic effect, these findings support the consideration of thromboembolism risk in clinical applications. Our results emphasize the importance of deciding between ADSCs and BMSCs based upon the target disease and culture method. [ABSTRACT FROM AUTHOR]

Hypoxia preconditioning enhances the paracrine abilities of mesenchymal stem cells (MSCs) for vascular regeneration and tissue healing. Implantation of hypoxia-induced mesenchymal stem cells (hi-MSCs) may further improve limb perfusion in a murine model of hindlimb ischemia. This study is aimed at determining whether implantation of hi-MSCs is an effective modality for improving outcomes of treatment of ischemic artery diseases. We evaluated the effects of human bone marrow-derived MSC implantation on limb blood flow in an ischemic hindlimb model. hi-MSCs were prepared by cell culture under 1% oxygen for 24 hours prior to implantation. A total of 1 × 10 5 MSCs and hi-MSCs and phosphate-buffered saline (PBS) were intramuscularly implanted into ischemic muscles at 36 hours after surgery. Restoration of blood flow and muscle perfusion was evaluated by laser Doppler perfusion imaging. Blood perfusion recovery, enhanced vessel densities, and improvement of function of the ischemia limb were significantly greater in the hi-MSC group than in the MSC or PBS group. Immunochemistry revealed that hi-MSCs had higher expression levels of hypoxia-inducible factor-1 alpha and vascular endothelial growth factor A than those in MSCs. In addition, an endothelial cell-inducing medium showed high expression levels of vascular endothelial growth factor, platelet endothelial cell adhesion molecule-1, and von Willebrand factor in hi-MSCs compared to those in MSCs. These findings suggest that pretreatment of MSCs with a hypoxia condition and implantation of hi-MSCs advances neovascularization capability with enhanced therapeutic angiogenic effects in a murine hindlimb ischemia model. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) have been reported to promote the regeneration of injured tissue via their paracrine abilities, which are enhanced by hypoxic preconditioning. In this study, we examined the therapeutic efficacy of hypoxia-preconditioned MSCs on renal fibrosis and inflammation in rats with ischemia-reperfusion injury (IRI). Methods: MSCs derived from rats and humans were incubated in 1% O2 conditions (1%O2 MSCs) for 24 h. After IRI, 1%O2 MSCs or MSCs cultured under normoxic conditions (21%O2 MSCs) were injected through the abdominal aorta. At 7 or 21 days post-injection, the rats were sacrificed and their kidneys were analyzed. In in vitro experiments, we examined whether 1%O2 MSCs enhanced the ability to produce anti-fibrotic humoral factors using transforming growth factor (TGF)-β1-stimulated HK-2 cells incubated with conditioned medium from MSCs. Results: Administration of rat 1%O2 MSCs (1%O2 rMSCs) attenuated renal fibrosis and inflammation more significantly than rat 21%O2 MSCs. Notably, human 1%O2 MSCs (1%O2 hMSCs) also attenuated renal fibrosis to the same extent as 1%O2 rMSCs. Flow cytometry showed that 1%O2 hMSCs did not change human leukocyte antigen expression. Further in vitro experiments revealed that conditioned medium from 1%O2 MSCs further suppressed TGF-β1-induced fibrotic changes in HK-2 cells compared with 21%O2 MSCs. Hypoxic preconditioning enhanced vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) secretion. Interestingly, VEGF knockdown in 1%O2 MSCs attenuated HGF secretion and the inhibition of TGF-β1-induced fibrotic changes in HK-2 cells. In addition, VEGF knockdown in 1%O2 hMSCs reduced the anti-fibrotic effect in IRI rats. Conclusions: Our results indicate that hypoxia-preconditioned MSCs are useful as an allogeneic transplantation cell therapy to prevent renal fibrosis and inflammation. [ABSTRACT FROM AUTHOR]

Background: Although malnutrition and bone fracture are both major complications in patients undergoing hemodialysis, their association has not been clarified. The aim of our study was to clarify the association between the geriatric nutritional risk index (GNRI), an indicator of nutritional status, and the incidence of bone fractures in patients undergoing hemodialysis. Methods: We included 1342 registered patients undergoing hemodialysis and performed a post hoc analysis. We divided patients into the high GNRI group (≥92), considered to have a low risk of malnutrition, and the low GNRI group (<92), considered to have a high risk of malnutrition. Fracture-free survival in the low and high GNRI groups was evaluated by the Kaplan–Meier method. Cox proportional hazards models were used to identify the risk factors for fractures requiring hospitalization. All results were stratified by sex. Results: New bone fractures developed in 108 (8.0%) patients in 5 years of follow-up. Bone fractures occurred more frequently in the low GNRI group compared with the high GNRI group (HR: 3.51, 95% CI: 1.91–6.42, p < 0.01 in males; HR: 2.47, 95% CI: 1.52–4.03, p < 0.01 in females). A low GNRI was significantly associated with an increased incidence of bone fractures, even after adjustment for covariates. However, the serum levels of calcium, phosphate, parathyroid hormone, and alkaline phosphatase were not associated with the incidence of bone fractures. Conclusions: A low GNRI is an independent risk factor for bone fractures in patients undergoing hemodialysis. Early intervention for the low GNRI group may be important in preventing the occurrence of fractures. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are a potential therapeutic tool for preventing the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). Herein, we investigated the localization and maintenance of engrafted human bone marrow-derived MSCs in rats subjected to a renal ischemia-reperfusion injury (IRI) and compared the effectiveness of two intravascular injection routes via the renal artery or inferior vena cava. Renal artery injection of MSCs was more effective than intravenous injection at reducing IRI-induced renal fibrosis. Additionally, MSCs injected through the renal artery persisted in injured kidneys for over 21 days, whereas MSCs injected through the inferior vena cava survived for less than 7 days. This difference may be attributed to the antifibrotic effects of MSCs. Interestingly, MSCs injected through the renal artery were localized primarily in glomeruli until day 3 post-IRI, and they decreased in number thereafter. In contrast, the number of MSCs localized in tubular walls, and the interstitium increased gradually until day 21 post-IRI. This localization change may be related to areas of damage caused by IRI because ischemia-induced AKI leads to tubular cell damage. Taken together, these findings suggest renal artery injection of MSCs may be useful for preventing the progression of AKI to CKD. [ABSTRACT FROM AUTHOR]

The transcription factors hypoxia-inducible factor-1α and -2α (HIF-1α/2α) are the major regulators of the cellular response to hypoxia and play a key role in renal fibrosis associated with acute and chronic kidney disease. Jumonji domain-containing 1a (JMJD1A), a histone H3 lysine 9 (H3K9) demethylase, is reported to be an important target gene of HIF-α. However, whether JMJD1A and H3K9 methylation status play a role in renal fibrosis is unclear. Here, we investigated the involvement of HIF-α, JMJD1A, and monomethylated/dimethylated H3K9 (H3K9me1/H3K9me2) levels in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Intraperitoneal administration of FG4592, an inhibitor of HIF-α prolyl hydroxylase, which controls HIF-α protein stability, significantly attenuated renal fibrosis on days 3 and 7 following UUO. FG4592 concomitantly increased JMJD1A expression, decreased H3K9me1/me2 levels, reduced profibrotic gene expression, and increased erythropoietin expression in renal tissues of UUO mice. The beneficial effects of FG4592 on renal fibrosis were inhibited by the administration of JMJD1A-specific siRNA to mice immediately following UUO. Incubation of normal rat kidney-49F and/or -52E cells with transforming growth factor-β1 (TGF-β1) in vitro resulted in upregulated expression of α-smooth muscle actin and H3K9me1/me2, and these effects were inhibited by cotreatment with FG4592. In contrast, FG4592 treatment further enhanced the TGF-β1-stimulated upregulation of JMJD1A but had no effect on TGF-β1-stimulated expression of the H3K9 methyltransferase euchromatic histone-lysine N -methyltransferase 2. Collectively, these findings establish a crucial role for the HIF-α1/2-JMJD1A-H3K9me1/me2 regulatory axis in the therapeutic effect of FG4592 in renal fibrosis. NEW & NOTEWORTHY Using a mouse model of renal fibrosis and transforming growth factor-β1-stimulated rat cell lines, we show that treatment with FG4592, an inhibitor of hypoxia-inducible factor-1α and -2α (HIF-1α/2α) prolyl hydroxylase decreases renal fibrosis and concomitantly reduces methylated lysine 9 of histone H3 (H3K9) levels via upregulation of Jumonji domain-containing 1a (JMJD1A). The results identify a novel role for the HIF-1α/2α-JMJD1A-H3K9 regulatory axis in suppressing renal fibrosis.