Background

Renal tubular injury, accompanied by damaging inflammation, has been identified to drive diabetic kidney disease (DKD) toward end-stage renal disease. However, it is unclear how damage-associated molecular patterns (DAMPs) activate innate immunity to mediate tubular epithelial cell (TEC) injury, which in turn causes with subsequent sterile inflammation in diabetic kidneys. High mobility group nucleosome-binding protein 1 (HMGN1) is a novel DAMP that contributes to generating the innate immune response. In this study, we focused on determining whether HMGN1 is involved in DKD progression.

Methods

Streptozotocin (STZ)-induced diabetic mice model was established. Then we downrergulated HMGN1 expression in kidney with or without HMGN1 administration. The renal dysfunction and morphological lesions in the kidneys were evaluated. The expressions of KIM-1, MCP-1, F4/80, CD68, and HMGN1/TLR4 signaling were examined in the renal tissue. In vitro, HK2 cells were exposed in the high glucose with or without HMGN1, and further pre-incubated with TAK242 was applied to elucidate the underlying mechanism.

Results

We demonstrated that HMGN1 was upregulated in the tubular epithelial cells of streptozotocin (STZ)-induced type 1 and type 2 diabetic mouse kidneys compared to controls, while being positively correlated with increased TLR4, KIM-1, and MCP-1. Down-regulation of renal HMGN1 attenuated diabetic kidney injury, decreased the TLR4, KIM-1, and MCP-1 expression levels, and reduced interstitial infiltrating macrophages. However, these phenotypes were reversed after administration of HMGN1. In HK-2 cells, HMGN1 promoted the expression of KIM-1 and MCP-1 via regulating MyD88/NF-κB pathway; inhibition of TLR4 effectively diminished the in vitro response to HMGN1.

Conclusions

Our study provides novel insight into HMGN1 signaling mechanisms that contribute to tubular sterile injury and low-grade inflammation in DKD. The study findings may help to develop new HMGN1-targeted approaches as therapy for immune-mediated kidney damage rather than as an anti-infection treatments.

中文翻译：

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糖尿病肾脏中 HMGN1 的下调可减轻肾小管细胞损伤，并通过 TLR4 抑制 MCP-1 和 KIM-1 表达来预防肾脏炎症

背景

肾小管损伤伴随着破坏性炎症，已被确定会导致糖尿病肾病 (DKD) 发展为终末期肾病。然而，目前尚不清楚损伤相关分子模式（DAMP）如何激活先天免疫以介导肾小管上皮细胞（TEC）损伤，进而导致糖尿病肾脏随后的无菌性炎症。高迁移率基团核小体结合蛋白 1 (HMGN1) 是一种新型 DAMP，有助于产生先天免疫反应。在本研究中，我们重点确定 HMGN1 是否参与 DKD 进展。

方法

建立链脲佐菌素(STZ)诱导的糖尿病小鼠模型。然后，我们在施用或不施用 HMGN1 的情况下下调肾脏中 HMGN1 的表达。评估肾功能障碍和肾脏形态学病变。检查肾组织中 KIM-1、MCP-1、F4/80、CD68 和 HMGN1/TLR4 信号传导的表达。在体外，HK2细胞暴露在有或没有HMGN1的高葡萄糖环境中，并进一步与TAK242预孵育以阐明其潜在机制。

结果

我们证明，与对照组相比，链脲佐菌素 (STZ) 诱导的 1 型和 2 型糖尿病小鼠肾脏的肾小管上皮细胞中 HMGN1 表达上调，同时与 TLR4、KIM-1 和 MCP-1 的增加呈正相关。肾脏 HMGN1 的下调可减轻糖尿病肾损伤，降低 TLR4、KIM-1 和 MCP-1 表达水平，并减少间质浸润巨噬细胞。然而，这些表型在施用 HMGN1 后发生逆转。在HK-2细胞中，HMGN1通过调节MyD88/NF-κB通路促进KIM-1和MCP-1的表达；TLR4 的抑制有效地减弱了对 HMGN1 的体外反应。

结论

我们的研究为 HMGN1 信号传导机制提供了新的见解，该机制导致 DKD 中肾小管不育损伤和低度炎症。该研究结果可能有助于开发新的 HMGN1 靶向方法作为免疫介导的肾脏损伤的治疗方法，而不是作为抗感染治疗。