Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, North Holland, The Netherlands.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
PLoS One. 2019 Mar 25;14(3):e0214437. doi: 10.1371/journal.pone.0214437. eCollection 2019.
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.
糖尿病肾病（DN）是糖尿病的一种微血管并发症，可导致肾小管和肾小球损伤。低度炎症和氧化应激是已知导致 DN 进展的两种机制。核苷酸结合富含亮氨酸重复序列家族成员 X1（NLRX1）是一种先天免疫受体，独特地位于线粒体中，已被发现通过调节氧化磷酸化来调节炎症反应和抑制肾脏氧化应激。出于这个原因，我们在 1 型糖尿病小鼠模型中研究了 NLRX1 在 DN 发展中的作用。我们分析了 NLRX1 缺乏对糖尿病发展以及伴随的肾脏损伤、炎症和纤维化的影响。我们发现，多次小剂量链脲佐菌素诱导体重减轻、多饮、高血糖、糖尿和野生型和 NLRX1 缺陷型小鼠轻度 DN 表型，但这些小鼠之间没有显著差异。尽管糖尿病野生型小鼠中 NLRX1 表达增加，但 NLRX1 缺乏并未影响链脲佐菌素处理诱导的糖尿病表型，这反映在野生型和 NLRX1 缺陷型小鼠的多尿、微量白蛋白尿以及增加的肾脏氧化应激和炎症标志物水平相似。目前的研究结果表明，在多次小剂量链脲佐菌素处理后，NLRX1 不会介导链脲佐菌素诱导的糖尿病和糖尿病诱导的肾病的发生。这一数据表明，虽然 NLRX1 可以被细胞应激触发，但它的调节和功能作用可能取决于特定的生理条件。在 DN 的情况下，NLRX1 可能既没有帮助也没有危害，而是代谢应激的标志物。
