Abstract
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.
Highlights
Alpha‐kinase 1 (ALPK1), a member of the alpha‐kinase family, has been reported to be highly associated with cancer and chronic diseases such as chronic kidney disease (CKD), type 2 diabetes mellitus and gout.[1-3]
The chemokine CCL2 and CCL5 expres‐ sions were up‐regulated in WT‐STZ, transgenic mice (TG) and TG‐STZ compared with the control groups significantly (P < .0001) (Figure 3)
Later studies indi‐ cated the associations between ALPK1 and many chronic diseases such as CKD, myocardial infarction, coronary artery disease and type 2 DM.[2,21-24]
Summary
Alpha‐kinase 1 (ALPK1), a member of the alpha‐kinase family, has been reported to be highly associated with cancer and chronic diseases such as chronic kidney disease (CKD), type 2 diabetes mellitus (type 2 DM) and gout.[1-3]. ALPK1 con‐ trols 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 infec‐ tions with Shigella flexneri, Salmonella typhimurium, Neisseria meningitides and Helicobacter pylori.[11,12] These observations suggest a master regulatory role of ALPK1 in inflammation and innate immunity. Streptozotocin (STZ)‐treated mice with ALPK1 overexpression exclusively showed severe hy‐ perglycaemia and accelerated multiple early nephropathies in the kidney.[10] Based on this evidence obtained from bacterial‐infected cell model, diabetic animal model and human studies of chronic diseases, ALPK1 has been proposed as a central player in the in‐ flammatory response. We discuss the regulation of chemokine by ALPK1 under high‐glucose condition and its importance in relation to renal inflammatory response
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