Diabetes Is Associated with Increased Autoreactivity of Mannan-Binding Lectin

Axelgaard, Esben; Østergaard, Jakob Appel; Thiel, Steffen; Hansen, Troels Krarup

doi:10.1155/2017/6368780

Cited by 29 publications

(28 citation statements)

References 30 publications

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“…Later studies have furthermore demonstrated a predictive role for high MBL serum levels for the development of micro- and macroalbuminuria [25]. In recent studies, we demonstrated that MBL indeed accumulates in the kidneys of diabetic mice with late vascular complications, thus strengthening the hypothesis of an autoreactive role of MBL in diabetic nephropathy [19, 20]. Our present findings further link the complement system to the pathophysiology of complications in type 1 diabetes.…”

Section: Discussionsupporting

confidence: 85%

“…In vitro studies have suggested that MBL is able to bind to hyperglycemia-induced neoepitopes of the Amadori type and activate complement [35, 36]. By two supplementary designed studies, we have recently found MBL to accumulate in the kidney in an in vivo IVIS study and in the glomerulus by immunofluorescence [19, 20]. As vascular tissue and organs throughout the body are exposed to hyperglycemia in diabetes, autoattack of MBL could potentially occur in several sites.…”

Section: Discussionmentioning

confidence: 99%

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Global Autorecognition and Activation of Complement by Mannan-Binding Lectin in a Mouse Model of Type 1 Diabetes

Axelgaard

Østergaard

Haxha

et al. 2017

Mediators of Inflammation

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Increasing evidence links mannan-binding lectin (MBL) to late vascular complications of diabetes. MBL is a complement-activating pattern recognition molecule of the innate immune system that can mediate an inflammation response through activation of the lectin pathway. In two recent animal studies, we have shown that autoreactivity of MBL is increased in the kidney in diabetic nephropathy. We hypothesize that long-term exposure to uncontrolled high blood glucose in diabetes may mediate formation of neoepitopes in several tissues and that MBL is able to recognize these structures and thus activate the lectin pathway. To test this hypothesis, we induced diabetes by injection of low-dose streptozotocin in MBL double-knockout (MBL/DKO) mice. Development of diabetes was followed by measurements of blood glucose and urine albumin-to-creatinine ratio. Fluorophore-labelled recombinant MBL was injected intravenously in diabetic and nondiabetic mice followed by ex vivo imaging of several organs. We observed that MBL accumulated in the heart, liver, brain, lung, pancreas, and intestines of diabetic mice. We furthermore detected increased systemic complement activation after administration of MBL, thus indicating MBL-mediated systemic complement activation in these animals. These new findings indicate a global role of MBL during late diabetes-mediated vascular complications in various tissues.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Global Autorecognition and Activation of Complement by Mannan-Binding Lectin in a Mouse Model of Type 1 Diabetes

Axelgaard

Østergaard

Haxha

et al. 2017

Mediators of Inflammation

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“…36 The increased level of mannose-binding lectin (MBL) regulates risk of developing microalbuminuria and DN. [37][38][39] In addition, Axelgaard et al 40 In conclusion, high-glucose stimulation enhances ALPK1 expression in the kidney in vitro and in vivo. Elevated ALPK1 expression up-regulates the renal levels of CCL2 and CCL5 in cultured kidney cell and in mice model.…”

Section: Discussionmentioning

confidence: 90%

“…The increased level of mannose‐binding lectin (MBL) regulates risk of developing microalbuminuria and DN . In addition, Axelgaard et al reported that MBL accumulates in the kidney during late DN. These results implicate the critical role of ALPK1 in the pathogenesis of renal injury in patients with chronic gout.…”

Section: Discussionmentioning

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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“…Which is well-defined as the presence of trace albuminuria followed by a diminished glomerular filtration rate (GFR) [2]. This signifies the inability of kidneys to prevent urinary protein leakage characterizes a significant primary sign of renal impairment in patients with T1DM [3]. One-third of T1DM patient's progress to DN, on the other hand, this incidence is much lower with T1DM [4].…”

Section: Introductionmentioning

confidence: 99%

Diabetic Nephropathy an Obvious Complication in Long Term Type 1 Diabetes Mellitus: A Case Study

Mohammad

Chigurupati

Othman

et al. 2017

Asian J Pharm Clin Res

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Most overwhelming complications of Type 1 diabetes mellitus patients are responsible for complications related to the microvascular system most likely with kidney. In the kidney, hyperglycemia induced microangiopathy resulting not only thickening of the glomerular capillary basement membrane but also to the proliferation of the mesangial matrix and solidifying of the tubular basement membrane. Several biochemical and pathological, factors are concerned for the development of diabetic renal microangiopathy. These include the glomerular hyperperfusion and hyperfiltration, transformed morphology of podocytes accompanies these basement membrane modifications, Type IV collagen augmented synthesis following the hyperglycemia, and increased expression of tissue matrix metalloproteinase. The aim of this case review is to highlight the recent advances in understanding the pathogenesis, diagnosis, the overview and the potential renoprotective therapeutic agents that would prevent the development or the progression of diabetic nephropathy.

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Diabetes Is Associated with Increased Autoreactivity of Mannan-Binding Lectin

Cited by 29 publications

References 30 publications

Global Autorecognition and Activation of Complement by Mannan-Binding Lectin in a Mouse Model of Type 1 Diabetes

Global Autorecognition and Activation of Complement by Mannan-Binding Lectin in a Mouse Model of Type 1 Diabetes

ALPK1 regulates streptozotocin‐induced nephropathy through CCL2 and CCL5 expressions

Diabetic Nephropathy an Obvious Complication in Long Term Type 1 Diabetes Mellitus: A Case Study

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