C1q/Tumor Necrosis Factor-Related Protein-9 Attenuates Diabetic Nephropathy and Kidney Fibrosis in db/db Mice

Hu, Hongyao; Li, Wei; Liu, Mingxin; Xiong, Jiarui; Li, Yanjun; Wei, Yanzhao; Huang, Congxin; Tang, Yuqi

doi:10.1089/dna.2019.5302

Cited by 14 publications

(11 citation statements)

References 46 publications

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“…Emerging evidence has recognized that CTRP9 may be a promising biomarker for microvascular and macrovascular complications of type 2 diabetes mellitus. Animal experiments demonstrated its role in attenuating diabetic retinopathy and nephropathy in db/db mice, which is in accordance with the vascular endothelial protective function of CTRP9 31 , 32 . Studies have also observed changes in serum CTRP9 levels in patients with type 2 diabetes mellitus and coronary artery disease, which is a macrovascular disease.…”

Section: Discussionsupporting

confidence: 77%

Association of serum CTRP9 levels with cardiac autonomic neuropathy in patients with type 2 diabetes mellitus

Yang

Dong

Chen

et al. 2021

J of Diabetes Invest

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Aims Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes and is associated with adipokines. The C1q tumor necrosis factor‐related protein 9 (CTRP9) is a newly discovered adipokine. This study aimed to evaluate the association of serum CTRP9 levels with the prevalence and severity of CAN in patients with type 2 diabetes mellitus. Materials and Methods We enrolled 262 patients (aged ≥18 years) with type 2 diabetes mellitus into this study. Standard cardiovascular autonomic reflex tests (CARTs) were used to assess CAN and patients were divided into three groups accordingly: a non‐CAN group, an early CAN group, and a definite CAN group. Serum CTRP9 levels were measured by enzyme‐linked immunosorbent assay, and the tertiles were calculated. Results Serum CTRP9 levels decreased significantly in the early CAN and definite CAN groups (P < 0.05). The percentage of definite CAN was the highest at the minimum tertile of serum CTRP9 level (T1; P < 0.05). Additionally, serum CTRP9 levels were negatively correlated with age, DM duration, hemoglobin A1c (HbA1c), and fasting plasma glucose (FPG) while positively correlated with high‐density lipoprotein cholesterol (HDL; P < 0.05). The level of CTRP9 was also significantly associated with the four indexes of CARTs (P < 0.05). Furthermore, CTRP9 was a protective factor for definite CAN (P < 0.05). Compared with the maximum tertile (T3) of the serum CTRP9 levels, a decreased level of serum CTRP9 in T1 significantly increased the prevalence ratio of definite CAN in patients with type 2 diabetes mellitus (P < 0.05). Conclusion Serum CTRP9 levels were independently associated with definite CAN. CTRP9 represents a reliable biomarker for exploring CAN in patients with type 2 diabetes mellitus.

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Section: Discussionsupporting

confidence: 77%

Association of serum CTRP9 levels with cardiac autonomic neuropathy in patients with type 2 diabetes mellitus

Yang

Dong

Chen

et al. 2021

J of Diabetes Invest

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“…Recent animal studies have shown that CTRP9 attenuates atherosclerosis through the inflammasome and autophagy signaling pathway in ApoE KO mice (Huang et al, 2019;Zhang et al, 2019). Furthermore, CTRP9 relieved hyperglycemia-mediated oxidative stress and apoptosis of endothelial cells in diabetic db/db mice (Hu et al, 2020). In our study, we aimed to explore whether the role of CTRP9 in atherosclerotic lesion formation is exerted through its antisenescence properties in vivo.…”

Section: Discussionmentioning

confidence: 98%

“…Our results indicated that CTRP9 mitigates endothelial cell senescence by influencing the expression of KLF4. CTRP9 has been shown to improve endothelial function and protect the macro-and microvasculature in diabetes via mechanisms that appear to be independent of its hypoglycemic actions (Cheng et al, 2016;Li et al, 2019;Hu et al, 2020). Although blood sugar levels of some patients with diabetes are well controlled, recent evidence indicates that transient hyperglycemia could potentiate persistent diabetic vascular complications and induce sustained endothelial senescence, a phenomenon known as "metabolic memory" (Zhang et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

C1q/TNF-Related Protein 9 Attenuates Atherosclerosis by Inhibiting Hyperglycemia-Induced Endothelial Cell Senescence Through the AMPKα/KLF4 Signaling Pathway

Wang

Han

Zhang³

et al. 2021

Front. Pharmacol.

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Hyperglycemia-induced endothelial cell senescence has been widely reported to be involved in the pathogenesis of type 2 diabetes mellitus‒accelerated atherosclerosis. Thus, understanding the underlying mechanisms and identifying potential therapeutic targets for endothelial cell senescence are valuable for attenuating atherosclerosis progression. C1q/tumor necrosis factor-related protein 9 (CTRP9), an emerging potential cardiokine, exerts a significant protective effect with respect to atherosclerosis, particularly in endothelial cells. However, the exact mechanism by which CTRP9 prevents endothelial cells from hyperglycemia-induced senescence remains unclear. This study aimed to investigate the effects of CTRP9 on hyperglycemia-induced endothelial cell senescence and atherosclerotic plaque formation in diabetic apolipoprotein E knockout (ApoE KO) mice. Human umbilical vein endothelial cells (HUVECs) were cultured in normal glucose (5.5 mM) and high glucose (40 mM) with or without recombinant human CTRP9 protein (3 μg/ml) for 48 h. Purified lentiviruses overexpressing CTRP9 (Lv-CTRP9) and control vectors containing green fluorescent protein (Lv-GFP) were injected via the tail vein into streptozotocin-induced diabetic ApoE KO mice. Results revealed that exposure of HUVECs to HG significantly increased the expression of Krüppel-like factor 4 (KLF4) and cyclin-dependent kinase inhibitor p21 (p21) and decreased that of telomerase reverse transcriptase (TERT). Treatment with recombinant human CTRP9 protein protected HUVECs from HG-induced premature senescence and dysfunction. CTRP9 promoted the phosphorylation of AMP-activated kinase (AMPK), attenuated the expression of KLF4 and p21 induced by HG, and increased the expression of TERT in HUVECs. Furthermore, in the background of AMPKα knockdown or KLF4 activation, the protective effects of CTRP9 were abolished. In-vivo experiments showed that the overexpression of CTRP9 inhibited vascular senescence and reduced atherosclerotic plaque formation in ApoE KO mice with diabetes. In conclusion, we demonstrate that KLF4 upregulation plays a crucial role in HG-induced endothelial senescence. This anti-atherosclerotic effect of CTRP9 may be partly attributed to the inhibition of HG-induced endothelial senescence through an AMPKα/KLF4-dependent mechanism, suggesting that CTRP9 could benefit further therapeutic approaches for type 2 diabetes mellitus‒accelerated atherosclerosis.

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“…Reduction of CTRP9 production during diabetes plays a causative role in platelet hyperactivity, contributing to platelet-induced diabetic cardiovascular damage 24 . CTRP9 attenuates diabetic nephropathy through ameliorating glomerular and tubular glycogen accumulation, fibrosis, hyperglycemia-mediated oxidative stress, and apoptosis in diabetic db/db mice 25 . CTRP9 regulates growth, differentiation, and apoptosis in human keratinocytes, providing a potentially effective therapeutic strategy for diabetic wounds 26 .…”

Section: Discussionmentioning

confidence: 99%

C1q/TNF-related Protein 9 Inhibits High Glucose–Induced Oxidative Stress and Apoptosis in Retinal Pigment Epithelial Cells Through the Activation of AMPK/Nrf2 Signaling Pathway

Cheng

Liu

et al. 2020

Cell Transplant

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Diabetic retinopathy (DR) is one of the common complications of diabetes mellitus. C1q/TNF-related protein 9 (CTRP9) has been demonstrated to be associated with the progression of diabetes and relative complications. However, its role in DR and underlying action of mechanism are not yet well understood. In the present study, human retinal pigment epithelial ARPE-19 cells were cultured under high concentration of glucose to simulate hyperglycemia condition in vitro. Our results showed that the expression of CTRP9 was significantly decreased in high glucose (HG)–stimulated ARPE-19 cells. CTRP9 overexpression improved HG-caused reduction in cell viability of ARPE-19 cells. CTRP9 overexpression significantly attenuated HG-induced oxidative stress, as proved by decreased levels of reactive oxygen species and malondialdehyde, and increased superoxide dismutase activity. Moreover, CTRP9 also prevented apoptosis in ARPE-19 cells in response to HG stimulation with decreased caspse-3 activity and bax expression, as well as increased bcl-2 expression. In contrast, knockdown of CTRP9 aggravated HG-induced oxidative stress and apoptosis. Furthermore, CTRP9 significantly induced the activation of AMPK/Nrf2 pathway in HG-induced ARPE-19 cells. Notably, inhibiting AMPK or Nrf2 blocked the protective effect of CTRP9 on ARPE-19 cells exposed to HG stimulation. Taken together, our findings suggested a protective effect of CTRP9 on HG-induced ARPE-19 cells and a putative mechanism involving the activation of AMPK/Nrf2 signaling pathway.

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C1q/Tumor Necrosis Factor-Related Protein-9 Attenuates Diabetic Nephropathy and Kidney Fibrosis in db/db Mice

Cited by 14 publications

References 46 publications

Association of serum CTRP9 levels with cardiac autonomic neuropathy in patients with type 2 diabetes mellitus

Association of serum CTRP9 levels with cardiac autonomic neuropathy in patients with type 2 diabetes mellitus

C1q/TNF-Related Protein 9 Attenuates Atherosclerosis by Inhibiting Hyperglycemia-Induced Endothelial Cell Senescence Through the AMPKα/KLF4 Signaling Pathway

C1q/TNF-related Protein 9 Inhibits High Glucose–Induced Oxidative Stress and Apoptosis in Retinal Pigment Epithelial Cells Through the Activation of AMPK/Nrf2 Signaling Pathway

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