NLRX1 does not play a role in diabetes nor the development of diabetic nephropathy induced by multiple low doses of streptozotocin

Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus that results in both tubular and glomerular injury. Low-grade inflammation and oxidative stress are two mechanisms known to drive the progression of DN. Nucleotide-binding leucine-rich repeat containing family member X1 (...

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Published in:PloS one Vol. 14; no. 3; p. e0214437
Main Authors: Scantlebery, Angelique M. L., Uil, Melissa, Butter, Loes M., Poelman, Renée, Claessen, Nike, Girardin, Stephen E., Florquin, Sandrine, Roelofs, Joris J. T. H., Leemans, Jaklien C.
Format: Journal Article
Language:English
Published: United States Public Library of Science 25.03.2019
Public Library of Science (PLoS)
Subjects:
Animals
Antioxidants
Authorship
Biology and Life Sciences
Body weight
Body weight loss
Butter
Cellular stress response
Diabetes
Diabetes mellitus
Diabetes mellitus (insulin dependent)
Diabetes Mellitus, Experimental - metabolism
Diabetes Mellitus, Experimental - pathology
Diabetic nephropathies
Diabetic Nephropathies - metabolism
Diabetic Nephropathies - pathology
Diabetic nephropathy
Dose-Response Relationship, Drug
Fibrosis
Glucose
Hemoglobin
Hyperglycemia
Inflammation
Kidney - drug effects
Kidney - metabolism
Kidney - pathology
Kidney diseases
Kidneys
Leucine
Male
Medicine and Health Sciences
Metabolism
Mice
Mice, Inbred C57BL
Microvasculature
Mitochondria
Mitochondrial Proteins - deficiency
Mitochondrial Proteins - metabolism
Nephropathy
Oxidative phosphorylation
Oxidative stress
Oxidative Stress - drug effects
Pathogenesis
Pathology
Phenotype
Phenotypes
Phosphorylation
Physiological effects
Polydipsia
Polyuria
Proteins
Streptozocin
Streptozocin - pharmacology
Tumor necrosis factor-TNF
Type 1 diabetes
Urination disorders
Weight loss
Netherlands
ISSN:1932-6203, 1932-6203
Online Access:Get full text
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Summary:Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus that results in both tubular and glomerular injury. Low-grade inflammation and oxidative stress are two mechanisms known to drive the progression of DN. Nucleotide-binding leucine-rich repeat containing family member X1 (NLRX1) is an innate immune receptor, uniquely located in mitochondria, that has been found to regulate inflammatory responses and to dampen renal oxidative stress by regulating oxidative phosphorylation. For this reason, we investigated the role of NLRX1 in the development of DN in a Type 1 Diabetes mouse model. We analyzed the effect of NLRX1 deficiency on diabetes development and the accompanied renal damage, inflammation, and fibrosis. We found that multiple low doses of streptozotocin induced body weight loss, polydipsia, hyperglycemia, glycosuria, and a mild DN phenotype in wildtype and NLRX1-deficient mice, without significant differences between these mouse strains. Despite increased NLRX1 expression in diabetic wildtype mice, NLRX1 deficiency did not affect the diabetic phenotype induced by streptozotocin treatment, as reflected by similar levels of polyuria, microalbuminuria, and increased renal markers of oxidative stress and inflammation in wildtype and NLRX1-deficient mice. The present findings show that NLRX1 does not mediate the development of streptozotocin-induced diabetes and diabetic-induced nephropathy in mice after multiple low doses of streptozotocin. This data implies that, while NLRX1 can be triggered by cellular stress, its regulatory and functional effects may be dependent on the specific physiological conditions. In the case of DN, NLRX1 may be neither helpful nor harmful, but rather a marker of metabolic stress.
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LMB, RP, NC also contributed equally to this work and JR and JL share last authorship.
Competing Interests: The authors have declared that no competing interests exist.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0214437