Abstract
Endoplasmic reticulum (ER) stress has been reported to play a pivotal role in diabetic nephropathy (DN). AdipoRon is a newly developed adiponectin receptor agonist that provides beneficial effects for diabetic mice; however, its underlying mechanism remains to be delineated. Here, we demonstrated increased expression levels of ER stress markers, accompanied by upregulated levels of proinflammatory cytokines and increased expression of collagen I, fibronectin, Bax, and cleaved caspase 3 in the kidneys of db/db mice compared with control mice. Decreased expression of adiponectin receptor 1 (AdipoR1) and phosphorylated 5′AMP-activated kinase (p-AMPK) was also observed in the kidneys of db/db mice. However, these alterations were partially reversed by intragastric gavage with AdipoRon. In vitro, AdipoRon alleviated high-glucose-induced ER stress, oxidative stress, and apoptosis in HK-2 cells, a human tubular cell line. Moreover, AdipoRon restored the expression of AdipoR1 and p-AMPK in HK-2 cells exposed to high-glucose conditions. Additionally, these effects were partially abrogated by pretreatment with AdipoR1 siRNA, but this abrogation was ameliorated by cotreatment with AICAR, an AMPK activator. Furthermore, the effects of AdipoRon were also partially abolished by cotreatment with compound C. Together, these results suggest that AdipoRon exerts favorable effects on diabetes-induced tubular injury in DN by inhibiting ER stress mediated by the AdipoR1/p-AMPK pathway.
Highlights
Diabetic nephropathy (DN) is the primary cause of end-stage renal disease for which better therapies are urgently needed [1]
Obvious decreases in albuminuria and in urinary oxidative stress marker 8-OHdG levels were observed in db/db mice treated with AdipoRon compared to those of db/db control mice and diabetic mice before the treatment (Figures 1(d) and 1(e))
Masson staining showed mildly increased interstitial fibrosis in db/db mice and those before the treatment compared with db/m mice, while this increase was reversed by AdipoRon treatment (Figure 1(g))
Summary
Diabetic nephropathy (DN) is the primary cause of end-stage renal disease for which better therapies are urgently needed [1]. Well-described characteristic pathophysiological features of DN include glomerular mesangial expansion and hypertrophy, tubular hypertrophy, and extracellular matrix deposition in the glomerular and tubulointerstitial compartments [2]. The pathogenesis of DN is still unclear, accumulating evidence has shown that endoplasmic reticulum (ER) stress plays a vital role in its onset and progression. The ER serves as a central site for folding, posttranslational modification, and transport of cellular proteins. Disruption of cellular homeostasis leads to the accumulation of misfolded and unfolded proteins, activating a signaling pathway referred to as the unfolded protein response (UPR). The three ER sensors, including protein kinase-like ER kinase (PERK), inositol requiring protein-1α (IRE1α), and activating transcription factor-6
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