Background
Although AKI is associated with an increased risk of CKD, the underlying mechanisms remain unclear. High mobility group box 1 (HMGB1), one of the ligands for the receptor for advanced glycation end products (RAGE), is elevated in patients with AKI. We recently demonstrated that the mineralocorticoid receptor (MR) is activated by the RAGE/Rac1 pathway, contributing to chronic renal damage in hypertensive mice. Therefore, this study investigated the role of the HMGB1/RAGE/MR pathway in AKI and progression to CKD.
Conclusions
Our findings suggest that HMGB1 may play a crucial role in AKI and CKD development by activating the Rac1/MR pathway through interactions with RAGE.
Methods
We performed a mouse model of renal ischemia–reperfusion (I/R) with or without MR antagonist (MRA). In vitro experiments were conducted using cultured endothelial cells to examine the interaction between the HMGB1/RAGE and Rac1/MR pathways.
Results
In renal I/R injury mice, renal MR activation was associated with elevated serum HMGB1, renal RAGE, and activated Rac1, all of which were suppressed by MRA. Renal I/R injury led to renal dysfunction, tubulointerstitial injury, and increased expressions of inflammation and fibrosis mediators, which were ameliorated by MRA. In vitro, RAGE aptamer or MRA inhibited HMGB1-induced Rac1/MR activation and upregulation of monocyte chemoattractant protein 1 and NF-κB expressions. Seven days after I/R injury, renal I/R injury mice developed CKD, whereas MRA prevented renal injury progression and decreased the mortality rate. Furthermore, in case of MRA treatment even after I/R injury, attenuated renal dysfunction compared with untreated mice was also observed. Conclusions: Our findings suggest that HMGB1 may play a crucial role in AKI and CKD development by activating the Rac1/MR pathway through interactions with RAGE.