Enhanced alpha-kinase 1 accelerates multiple early nephropathies in streptozotocin-induced hyperglycemic mice

Kuo, Tzer‐Min; Hsu, Hui‐Ting; Chung, Chia Min; Yeh, Kun‐Tu; Wu, Cheng-Tien; Lee, Chi‐Pin; Chiang, Shang-Lun; Huang, Chung‐Ming; Ko, Ying‐Chin

doi:10.1016/j.bbadis.2016.08.010

Cited by 13 publications

(21 citation statements)

References 41 publications

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“…Previous study showed that after three weeks of perfusion with glyoxal in rats, the kidney was damaged and the protein expression level of TGF‐β in the kidney tissue was significantly increased [51] . In addition, α‐protein kinase 1 accelerated the development of kidney disease by increasing the expression of TGF‐β1 in HEK293 cells [52] . The results indicated the significant role of TGF‐β1 in nephropathy, and MGO might aggravate kidney damage by increasing the expression of TGF‐β1 protein.…”

Section: Resultsmentioning

confidence: 99%

Potential Mechanisms of Methylglyoxal‐Induced Human Embryonic Kidney Cells Damage: Regulation of Oxidative Stress, DNA Damage, and Apoptosis

Liú

Cheng

Tang

et al. 2022

Chemistry & Biodiversity

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Methylglyoxal (MGO) is a reactive carbonyl species that can cause cellular damage and is closely related to kidney disease, especially diabetic nephropathy. The toxic effect of MGO (0.5, 1, and 2 mM) on human embryonic kidney (HEK293) cells and its underlying mechanisms were explored in this study. Cell viability, apoptosis and the signaling pathways were measured with MTT, fluorescent staining and western blot experiments, the results showed that MGO could induce oxidative stress and cell inflammation, the level of reactive oxygen species (ROS) increased, and p38MAPK, JNK and NF‐κB signaling pathways were activated. Meanwhile, MGO also induced DNA damage. The expression of DNA oxidative damage marker 8‐hydroxy‐2’‐deoxyguanosine (8‐OHdG) increased, the expression of double‐strand break marker γH2AX increased significantly, and ATM/Chk2/p53 DNA damage response signaling pathway was activated. Furthermore, the expression of the receptor for advanced glycation end products (RAGE) also increased. Finally, mitochondrial membrane potential (MMP) decreased, fluorescence intensity of Hoechst33258 increased, and the protein expression ratio of Bax/Bcl‐2 increased significantly after the treatment of MGO. These results demonstrated that MGO might induce HEK293 cells damage by regulating oxidative stress, inflammation, DNA damage, and cell apoptosis, which revealed the specific mechanisms of MGO‐induced damage to HEK293 cells.

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Section: Resultsmentioning

confidence: 99%

Potential Mechanisms of Methylglyoxal‐Induced Human Embryonic Kidney Cells Damage: Regulation of Oxidative Stress, DNA Damage, and Apoptosis

Liú

Cheng

Tang

et al. 2022

Chemistry & Biodiversity

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“…A previous study have showed that C57BL/6 mice with Alpk1 overexpression exhibited normal blood glucose level. After MLDS treatment, those mice showed a lower level of insulin and severe hyperglycemia ( 13 ). In line with this observation, we found that Alpk1 activation alone did not alter the proliferation or apoptosis of MIN6 cells.…”

Section: Discussionmentioning

confidence: 99%

“…So far, the role of ALPK1 in beta cell survival and function is little known. A recent paper has shown that Alpk1 -overexpressed C57BL/6 mice exhibited a decreased insulin level and severe hyperglycaemia than wild type mice after streptozotocin (STZ) treatment ( 13 ), suggesting that Alpk1 might participate in the destruction of pancreatic beta cells. Therefore, in this study we investigated the role of Alpk1 in the injury of MIN6 cells, a murine pancreatic beta cell line.…”

Section: Introductionmentioning

confidence: 99%

“…Alpha-kinase 1 (ALPK1, also known lymphocyte a-kinase) has been recently identified as a new cytosolic PRR specific for ADP-b-D-manno-heptose (ADP-heptose), a metabolite in the biosynthesis of Lipopolysaccharide (LPS) (9). A series of studies have demonstrated that ALPK1 is an upstream kinase to induce the phosphorylation and oligomerization of RAF-interacting protein with forkhead-associated domain (TIFA), and subsequently TGF-b-activated kinase 1 (TAK1) phosphorylation, nuclear factor kappa B (NF-kB) activation and pro-inflammatory cytokine production (10)(11)(12)(13), suggesting that ALPK1 is an essential player in inflammation and innate immune responses.…”

Section: Introductionmentioning

confidence: 99%

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Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway

Ding

Luo

et al. 2021

Front. Immunol.

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Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-β-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.

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“…ALPK1 is also known to be involved in the phosphorylation of myosin IA and myosin IIA, which might participate in apical protein transport and TNF‐α secretion . ALPK1 enhances the expression of proinflammatory cytokines including IL‐1β, IL‐8 and TGF‐β1 in cultured human THP1 and human embryonic kidney 293 (HEK293) cells . ALPK1 controls the formation of the TIFA complex, which acts in a sequential manner to activate the transcription factor nuclear factor‐kappaB (NFkB) and regulate the production of IL‐8 in response to infections with Shigella flexneri , Salmonella typhimurium , Neisseria meningitides and Helicobacter pylori .…”

Section: Introductionmentioning

confidence: 99%

ALPK1 regulates streptozotocin‐induced nephropathy through CCL2 and CCL5 expressions

Lee

Nithiyanantham

Hsu

et al. 2019

J Cellular Molecular Medi

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ALPK1 is associated with chronic kidney disease, gout and type 2 diabetes mellitus. Raised renal ALPK1 level in patients with diabetes was reported. Accelerated fibrotic nephropathies were observed in hyperglycaemic mice with up‐regulated ALPK1. The aim of this study was to identify the mediators contributing to ALPK1 effect involving in nephropathies induction. The haematoxylin and eosin staining, Masson's trichrome and immunohistochemical analysis of ALPK1, NFkB, CCL2 and CCL5 were performed in the mice kidney. Cytokine antibody array analysis was performed in streptozotocin‐treated wild‐type mice (WT‐STZ) and streptozotocin‐treated ALPK1 transgenic mice (TG‐STZ). The ALPK1 levels were measured in mice kidney and in cultured cells. We found that the higher levels of renal CCL2/MCP‐1, CCL5/Rantes and G‐CSF expression in TG‐STZ compared with the WT‐STZ. Glucose increased ALPK1 expressions in monocytic THP1 and human kidney‐2 cells. The protein expression of ALPK1, NFkB and lectin was up‐regulated in glucose‐treated HK‐2 cells. Knockdown of ALPK1 reduced CCL2 and CCL5 mRNA levels, whereas overexpressed ALPK1 increased CCL2 and CCL5 in cultured kidney cells. Taken together, these results show that high glucose increases ALPK1 and chemokine levels in the kidney. Elevated ALPK1 expression enhances renal CCL2 and CCL5 expressions in vivo and in vitro. ALPK1 is a mediator for CCL2 and CCL5 chemokine up‐regulation involving in diabetic nephropathies induction.

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Enhanced alpha-kinase 1 accelerates multiple early nephropathies in streptozotocin-induced hyperglycemic mice

Cited by 13 publications

References 41 publications

Potential Mechanisms of Methylglyoxal‐Induced Human Embryonic Kidney Cells Damage: Regulation of Oxidative Stress, DNA Damage, and Apoptosis

Potential Mechanisms of Methylglyoxal‐Induced Human Embryonic Kidney Cells Damage: Regulation of Oxidative Stress, DNA Damage, and Apoptosis

Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway

ALPK1 regulates streptozotocin‐induced nephropathy through CCL2 and CCL5 expressions

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