Renal Klotho is Reduced in Septic Patients and Pretreatment With Recombinant Klotho Attenuates Organ Injury in Lipopolysaccharide-Challenged Mice

Jou-Valencia, Daniela; Molema, Grietje; Popa, Eliane R.; Aslan, Adnan; Dijk, F; Mencke, Rik; Hillebrands, Jan-Luuk; Heeringa, Peter; Hoenderop, Joost G. J.; Zijlstra, Jan G.; Meurs, Matijs van; Moser, Jill

doi:10.1097/ccm.0000000000003427

Cited by 25 publications

(23 citation statements)

References 57 publications

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“…The results show that both mRNA and protein levels of α -klotho in mouse hearts were undetectable, while the expressions were very high in the mouse kidney. Recent studies have found that the renal α -klotho expression was reduced in patients with sepsis-induced acute kidney injury, while renal damage markers, such as NGAL and KIM-1, were increased [15], which is consistent with our findings. In our studies, after injection of LPS, the levels of α -klotho in the kidneys were significantly reduced as early as 6 h. The decrease in renal α -klotho has also been shown in several other animal models, such as renal ischemia-reperfusion injury [16], the db/db mouse model of diabetes [17], the unilateral ureteral ligation (UUO) model [18], and the cisplatin-induced AKI model [19], which indicates that the kidney was the main source of α -klotho.…”

Section: Discussionsupporting

confidence: 92%

“…Previous studies showed that α -klotho deficiency may aggravate heart and kidney injuries when exposed to damage, while supplementation of α -klotho could attenuate AKI and stress-induced cardiac hypertrophy [11, 13, 16]. Recent studies showed that the administration of recombinant α -klotho protects against LPS-induced kidney damage and attenuates LPS-mediated endothelial activation [15]. In our study, pretreatment with α -klotho significantly ameliorates acute cardiorenal injury.…”

Section: Discussionsupporting

confidence: 66%

“…Cytokines play crucial roles in the initiation and resolution of inflammation in sepsis. Recent studies showed that pretreatment with α -klotho decreased the renal cytokine IL-6, IL-8, and MCP levels [15]. In patients with CKD, the resolution of inflammation secondary to intercurrent septic processes goes along with a doubling in the levels of circulating iFGF23 and a downregulation of α -klotho.…”

Section: Discussionmentioning

confidence: 99%

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Recombinant α-Klotho Protein Alleviated Acute Cardiorenal Injury in a Mouse Model of Lipopolysaccharide-Induced Septic Cardiorenal Syndrome Type 5

Niu

Zhang

et al. 2019

Analytical Cellular Pathology

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Background and Aims. Klotho is an aging-suppressor gene mainly expressed in the renal tubules. The klotho gene encodes the α-klotho protein, which has many functions. Previous studies have found that α-klotho protein has a cardiorenal protective function. α-Klotho deficiency renders the kidney more susceptible to injury and results in cardiovascular calcification and left ventricular hypertrophy in chronic kidney disease. However, the role of α-klotho in acute heart injury and acute kidney injury with sepsis remains unknown. This study aimed to investigate the effects and mechanisms of α-klotho in septic cardiorenal injury. Methods. Male 8-week-old C57BL/6 mice were randomly assigned to the control group, lipopolysaccharide (LPS; 10 mg/kg) group, LPS (10 mg/kg)+α-klotho (0.01 mg/kg) group, and LPS (10 mg/kg)+α-klotho (0.02 mg/kg) group. Recombinant α-klotho was intraperitoneally injected an hour before LPS injection. Mice were euthanized at 24 h after LPS injection. The serum troponin, brain natriuretic peptide (BNP), neutrophil gelatinase-associated lipocalin (NGAL), and creatinine levels were measured in all groups at 24 h. Biomarkers of mice heart apoptosis, inflammation, oxidative stress, and endoplasmic reticulum stress, such as caspase-3, interleukin 1 (IL-1), reactive oxygen species (ROS), and glucose-regulated protein 78 (GRP78), were also measured. Results. α-Klotho was mainly expressed in mice kidneys and was undetectable in the control mice hearts. α-Klotho substantially decreased after LPS injection. In the LPS group, the serum troponin levels significantly increased as early as 6 h (p<0.05) after LPS injection, while the BNP, NGAL, and creatinine levels significantly increased at 24 h (p<0.05). Pretreatment with α-klotho significantly ameliorated acute cardiorenal injury. In the LPS+α-klotho (0.01 mg/kg) group, the levels of apoptosis, inflammation, and oxidative stress were decreased, while the level of endoplasmic reticulum stress was elevated. Conclusions. α-Klotho significantly alleviates acute cardiorenal injury in LPS-induced septic cardiorenal injury due to the inhibition of apoptosis, inflammation, and oxidation, as well as the regulation of endoplasmic reticulum stress levels.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Recombinant α-Klotho Protein Alleviated Acute Cardiorenal Injury in a Mouse Model of Lipopolysaccharide-Induced Septic Cardiorenal Syndrome Type 5

Niu

Zhang

et al. 2019

Analytical Cellular Pathology

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“…LPS, a known toxic component of Gram-negative bacteria, is widely used to induce SAKI in animal models (Jou-Valencia et al, 2018), and studies have confirmed that the intraperitoneal administration of LPS for 4 h induces AKI (Chen et al, 2019;Feng et al, 2019). After LPS treatment, the indicators of kidney injury (BUN, Cre, KIM-1, and NGAL) are significantly increased, suggesting renal dysfunction and kidney injury.…”

Section: Discussionmentioning

confidence: 97%

Dexmedetomidine Protects Against Lipopolysaccharide-Induced Acute Kidney Injury by Enhancing Autophagy Through Inhibition of the PI3K/AKT/mTOR Pathway

Zhao

Feng

et al. 2020

Front. Pharmacol.

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Background: Acute kidney injury (AKI) is often secondary to sepsis. Previous studies suggest that damaged mitochondria and the inhibition of autophagy results in AKI during sepsis, but dexmedetomidine (DEX) alleviates lipopolysaccharide (LPS)-induced AKI. However, it is uncertain whether the renoprotection of DEX is related to autophagy or the clearance of damaged mitochondria in sepsis-induced AKI. Methods: In this study, AKI was induced in rats by injecting 10 mg/kg of LPS intraperitoneally (i.p.). The rats were also pretreated with DEX (30 mg/kg, i.p.) 30 min before the injection of LPS. The structure and function of kidneys harvested from the rats were evaluated, and the protein levels of autophagy-related proteins, oxidative stress levels, and apoptosis levels were measured. Further, atipamezole (Atip) and 3-Methyladenine (3-MA), which are inhibitors of DEX and autophagy, respectively, were administered before the injection of DEX to examine the protective mechanism of DEX. Results: Pretreatment with DEX ameliorated kidney structure and function. DEX decreased the levels of blood urea nitrogen (BUN) and creatinine (Cre), urine kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), reactive oxygen species (ROS), and apoptosis proteins (such as cleaved caspase-9 and cleaved caspase-3). However, DEX upregulated the levels of autophagy and mitophagy proteins, such as Beclin-1, LC3 II and PINK1. These results suggest that DEX ameliorated LPS-induced AKI by reducing oxidative stress and apoptosis and enhancing autophagy. To promote autophagy, DEX inhibited the phosphorylation levels of PI3K, AKT, and mTOR. Furthermore, the administration of Atip and 3-MA inhibitors blocked the renoprotection effects of DEX. Conclusions: Here, we demonstrate a novel mechanism in which DEX protects against LPS-induced AKI. DEX enhances autophagy, which results in the removal of damaged

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“…Male C57BL/6 mice purchased from Envigo (Horst, The Netherlands) and housed in a specific pathogen-free facility, maintained on chow and water ad libitum , and housed in temperature-controlled chambers (24°C) with a 12 h light/dark cycle. Mice were challenged with intraperitoneal (i.p) injection of 1 mg/kg LPS [ E. coli , serotype O26:B6 (15,000 EU/g), Sigma-Aldrich, St. Louis, MO, USA] as described elsewhere (14). Control mice were i.p administered with the same volume of 0.9% NaCl.…”

Section: Methodsmentioning

confidence: 99%

Identification of LPS-Activated Endothelial Subpopulations With Distinct Inflammatory Phenotypes and Regulatory Signaling Mechanisms

et al. 2019

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Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Endothelial cells (EC) are actively involved in sepsis-associated (micro)vascular disturbances and subsequent organ dysfunction. Lipopolysaccharide (LPS), a Gram-negative bacterial product, can activate EC leading to the expression of pro-inflammatory molecules. This process is molecularly regulated by specific receptors and distinct, yet poorly understood intracellular signaling pathways. LPS-induced expression of endothelial adhesion molecules E-selectin and VCAM-1 in mice was previously shown to be organ- and microvascular-specific. Here we report that also within renal microvascular beds the endothelium expresses different extents of E-selectin and VCAM-1. This heterogeneity was recapitulated in vitro in LPS-activated human umbilical vein EC (HUVEC). Within 2 h after LPS exposure, four distinct HUVEC subpopulations were visible by flow cytometric analysis detecting E-selectin and VCAM-1 protein. These encompassed E-selectin − /VCAM-1 − (–/–), E-selectin + /VCAM-1 − (E-sel+), E-selectin + /VCAM-1 + (+/+), and E-selectin − /VCAM-1 + (VCAM-1+) subpopulations. The formation of subpopulations was a common response of endothelial cells to LPS challenge. Using fluorescence-activated cell sorting (FACS) we demonstrated that the +/+ subpopulation also expressed the highest levels of inflammatory cytokines and chemokines. The differences in responsiveness of EC subpopulations could not be explained by differential expression of LPS receptors TLR4 and RIG-I. Functional studies, however, demonstrated that the formation of the E-sel+ subpopulation was mainly TLR4-mediated, while the formation of the +/+ subpopulation was mediated by both TLR4 and RIG-I. Pharmacological blockade of NF-κB and p38 MAPK furthermore revealed a prominent role of their signaling cascades in E-sel+ and +/+ subpopulation formation. In contrast, the VCAM-1+ subpopulation was not controlled by any of these signaling pathways. Noteworthy is the existence of a “quiescent” subpopulation that was devoid of the two adhesion molecules and did not express cytokines or chemokines despite LPS exposure. Summarizing, our findings suggest that LPS activates different signaling mechanisms in EC that drive heterogeneous expression of EC inflammatory molecules. Further characterization of the signaling pathways involved will enhance our understanding of endothelial heterogeneous responses to sepsis related stimuli and enable the future design of effective therapeutic strategies to interfere in these processes to counteract sepsis-associated organ dysfunction.

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Renal Klotho is Reduced in Septic Patients and Pretreatment With Recombinant Klotho Attenuates Organ Injury in Lipopolysaccharide-Challenged Mice

Abstract: Supplemental Digital Content is available in the text.

Cited by 25 publications

References 57 publications

Recombinant α-Klotho Protein Alleviated Acute Cardiorenal Injury in a Mouse Model of Lipopolysaccharide-Induced Septic Cardiorenal Syndrome Type 5

Recombinant α-Klotho Protein Alleviated Acute Cardiorenal Injury in a Mouse Model of Lipopolysaccharide-Induced Septic Cardiorenal Syndrome Type 5

Dexmedetomidine Protects Against Lipopolysaccharide-Induced Acute Kidney Injury by Enhancing Autophagy Through Inhibition of the PI3K/AKT/mTOR Pathway

Identification of LPS-Activated Endothelial Subpopulations With Distinct Inflammatory Phenotypes and Regulatory Signaling Mechanisms

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