Advertisement

ResearchIn-Press PreviewEndocrinologyNephrology Open Access | 10.1172/jci.insight.187653

RasGRP4 aggravates ischemia-reperfusion injury in diabetic kidneys by mediating communication between macrophages and T cells

Li Zhang,1 Zhanglong Wang,1 Yunqi Wu,1 Binshan Zhang,1 Zhongli Wang,1 Sisi Chen,1 Mengxu Ying,1 Pei Yu,1 and Saijun Zhou1

1Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China

Find articles by Zhang, L. in: JCI | PubMed | Google Scholar

1Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China

Find articles by Wang, Z. in: JCI | PubMed | Google Scholar

1Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China

Find articles by Wu, Y. in: JCI | PubMed | Google Scholar

1Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China

Find articles by Zhang, B. in: JCI | PubMed | Google Scholar

1Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China

Find articles by Wang, Z. in: JCI | PubMed | Google Scholar

1Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China

Find articles by Chen, S. in: JCI | PubMed | Google Scholar

1Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China

Find articles by Ying, M. in: JCI | PubMed | Google Scholar

1Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China

Find articles by Yu, P. in: JCI | PubMed | Google Scholar

1Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China

Find articles by Zhou, S. in: JCI | PubMed | Google Scholar

Published December 10, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.187653.
Copyright © 2024, Zhang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 10, 2024 - Version history
View PDF
Abstract

Diabetes mellitus (DM) is acknowledged as an independent risk factor for acute kidney injury. Ras guanine nucleotide-releasing protein-4 (RasGRP4) exerts a notable role in modulating immune-inflammatory responses and kidney disease progression in diabetes. Herein, we delved into the specific role and mechanism of RasGRP4 in diabetic renal ischemia-reperfusion injury. Diabetes was induced by a high-fat diet and STZ injections, followed by creating an ischemia-reperfusion kidney injury via renal pedicle clamping and reperfusion. In vitro, a high glucose and hypoxia-reoxygenation modeled cellular inflammatory injury. We found RasGRP4 knockout (KO) mice, compared to C57BL/6J (WT) mice, showed markedly less renal dysfunction and fibrosis in diabetic ischemia-reperfusion injury. There was a significant decrease in the renal infiltration of M1 macrophages and Th17 cells, along with downregulated IL17 pathway proteins and effectors. In vitro, RasGRP4 deletion restrained M1 macrophage polarization and Th17 cell differentiation, inhibiting the IL17 signaling pathway in HK-2 cells. Hyperglycemia intensified renal inflammation state. Together, RasGRP4, through the regulation of interactions among M1 macrophages, CD4+ T cells and HK-2 cells, formed a cascade that intensified the inflammatory storm activity, ultimately exacerbating the inflammatory injury of diabetic ischemia-reperfusion kidneys. DM intensified this inflammatory injury mechanism, worsening the injury from renal ischemia-reperfusion.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View Supplemental data

Version history
  • Version 1 (December 10, 2024): In-Press Preview
Advertisement
Advertisement