ELABELA and an ELABELA Fragment Protect against AKI

Chen, Hong; Wang, Lin; Wang, Wenjun; Cheng, Cheng; Zhang, Yu; Zhou, Yu; Wang, Cong Yi; Miao, Xiaoping; Wang, Jiao; Wang, Chao; Li, Jianshuang; Zheng, Ling; Huang, Kun

doi:10.1681/asn.2016111210

Cited by 115 publications

(155 citation statements)

References 51 publications

(85 reference statements)

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“…Slowly, the biological functions of ELA are starting to be revealed. Chen et al [13]. reported that ELA treatment markedly improves acute kidney injury in vitro and in vivo through inhibiting apoptosis, reducing inflammatory response, suppressing fibrosis and related markers (TGF-β1, fibronectin, vimentin, and collagen 1), and decreasing autophagy and the DNA damage response.…”

Section: Discussionmentioning

confidence: 99%

Serum Elabela/Toddler Levels Are Associated with Albuminuria in Patients with Type 2 Diabetes

Zhang

Gong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Elabela (ELA) or Toddler is a recently identified hormone that plays a crucial role in embryonic development through the activation of the apelin receptor (APJ). Our previous study indicated that ELA is highly expressed in adult kidney and the ELA receptor signaling pathway is functional in mammalian systems. Whereas nothing is yet known regarding ELA and diabetic kidney disease (DKD). Here, we evaluated the relationship between serum ELA levels and albuminuria in patients with type 2 diabetes (T2D). Methods: An observational study involving 80 patients divided into groups according to their baseline urinary albumin/creatinine ratio (ACR): Group 1 (ACR ≤ 29 mg/g), Group 2 (ACR = 30–299 mg/g), Group 3 (ACR ≥ 300 mg/g with normal serum creatinine), and Group 4 (ACR ≥ 300 mg/g with increased serum creatinine). The demographic, clinical, and biochemical variables including serum ELA were obtained or measured through disease history, physical examination, or laboratory evidence. Results: The results showed that the serum ELA levels decreased gradually with the deterioration of DKD from the stages of normal albuminuria, microalbuminuria, macroalbuminuria, to macroalbuminuria and elevated serum creatinine. In addition, ELA had a significantly negative correlation with ACR (r = -0.561, P < 0.001), retinopathy (r = -0.424, P < 0.001), serum creatinine (r = -0.269, P = 0.016), SBP (r = -0.249, P = 0.026), DBP (r = -0.261, P = 0.020) and a positive correlation with eGFR (r = 0.318, P = 0.004). Furthermore, stepwise multiple linear regression analysis showed that ACR, retinopathy, and LDL-C were considered the most relevant variables to ELA, and ELA, retinopathy, eGFR, and age were important predictors for ACR (t = -4.546, P = 0.000). Conclusions: To our knowledge, this is the first study to explore the clinical relationship between ELA levels and CKD. Decreased serum ELA levels might be a significant clinical predictor in patients with DKD or even as a promising agent for treating CKD patients.

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Section: Discussionmentioning

confidence: 99%

Serum Elabela/Toddler Levels Are Associated with Albuminuria in Patients with Type 2 Diabetes

Zhang

Gong

et al. 2018

Cell Physiol Biochem

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“…Sections and cells were detected by TUNEL assay using an In Situ Cell Death Detection Kit (Roche, Mannheim, Germany) as described previously (Chen et al . ). DHE staining (Beyotime, Shanghai, China), a marker for oxidative stress, was performed on renal cryosections.…”

Section: Methodsmentioning

confidence: 97%

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Hong

Huang

Xiu-qin

et al. 2018

The Journal of Physiology

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Key points Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients. In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid‐induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. We found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal abnormalities in db/db mice, an animal model of type 2 diabetes. These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. Abstract Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end‐stage kidney disease worldwide without effective therapy available. UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase that removes the di‐ and tri‐methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control and life span regulation in Caenorhabditis elegans. In the present study, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, comprising an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD.

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“…For immunofluorescence staining, primary antibody against PDGFRα (AF1062, 1:200 dilution, R&D Systems) or Ki67 (sc15402, 1:100 dilution, Santa Cruz) was applied overnight. The sections were then incubated with anti‐goat or anti‐rabbit secondary antibody followed by DAPI staining, and images were taken . The number of cells with positive staining for both Ki67 and PDGFRα per field was determined.…”

Section: Methodsmentioning

confidence: 99%

“…The sections were then incubated with anti-goat or anti-rabbit secondary antibody followed by DAPI staining, and images were taken. 20,21 The number of cells with positive staining for both Ki67 and PDGFRα per field was determined.…”

Section: Histological Immunohistochemical Staining and Immunofluomentioning

confidence: 99%

Lmo4‐resistin signaling contributes to adipose tissue‐liver crosstalk upon weight cycling

et al. 2020

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Repeated cycles of weight loss and regain, known as weight cycling, is often seen when people try to lose weight. The exact pathophysiological effects and the underlying mechanisms of weight cycling remain largely unclear. Here, we report that weight cycling induced by alternating feeding mice with a low‐fat diet or a high‐fat diet in a 1‐week switch protocol caused further increased epididymal white adipose tissue (eWAT) weight, preadipocyte proliferation, hepatic inflammation, fasting blood glucose level, and glucose intolerance, compared with the continuously HF‐fed mice. Combining the secretory protein database with RNA‐sequencing and quantitative PCR (qPCR) results in eWAT, the mRNA levels of several adipokines, including Retn (encoding resistin), were found altered by weight cycling. A transcriptional co‐factor Lmo4 was found regulated by weight cycling; Lmo4 enhanced preadipocyte proliferation, in vitro adipogenesis, transcription of Retn, and resistin secretion in 3T3‐L1 cells. Primary mouse hepatocytes administrated with recombinant mouse resistin (rm‐resistin), or exposed to media from Lmo4‐overexpressed 3T3‐L1 cells, showed increased inflammatory responses and gluconeogenesis. Furthermore, rm‐resistin‐injected normal chow‐fed mice showed upregulated blood glucose level by increasing gluconeogenesis, and upregulated the hepatic inflammatory responses. Together, our results suggest a regulatory role of Lmo4‐resistin signaling in weight cycling, indicating a crosstalk between the adipose tissue and liver.

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ELABELA and an ELABELA Fragment Protect against AKI

Cited by 115 publications

References 51 publications

Serum Elabela/Toddler Levels Are Associated with Albuminuria in Patients with Type 2 Diabetes

Serum Elabela/Toddler Levels Are Associated with Albuminuria in Patients with Type 2 Diabetes

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Lmo4‐resistin signaling contributes to adipose tissue‐liver crosstalk upon weight cycling

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