AdipoRon is an orally active synthetic small molecule that

AdipoRon is an orally active, synthetic small molecule that activates adiponectin receptor (AdipoR). It mimics the antidiabetic effects of adiponectin, exhibiting its effect through the activation of AMPK and PPARα pathways via AdipoR1 and AdipoR2, respectively (Fig. 2) [62]. AdipoR activation has recently become a promising treatment for diabetes, nonalcoholic fatty liver disease, and cardiovascular disease, demonstrating anti-inflammatory actions in macrophages and cytoprotective effects on pancreatic β-cells [63]. However, mice overexpressing adiponectin are found to have reduced bone density [64], heart damage (left ventricular hypertrophy) [65], increased angiogenesis and adipogenesis [65], and infertility [66]. Despite these concerns, AdipoRon appears to be weight neutral and actually prolongs the life span in db/db mice [62]. Our unpublished data suggest that AdipoRon-treated db/db mice exhibit improvements in DN associated with increased expression of AdipoR1 and AdipoR2 in the glomerulus and consistent upregulation of phosphorylated AMPK, PPARα, and their downstream target molecules (unpublished observations). With respect to renal ultrastructure, AdipoRon treatment is associated with a noticeable reversal of diabetes-induced glomerular basement membrane (GBM) thickening, foot process widening, and slit why space narrowing; furthermore, it decreased glomerular matrix expansion and inflammation. AdipoRon may control oxidative stress in the glomerulus through AMPK- and PPARα-activated pathways, helping to prevent the deterioration of renal function. The protective role of AdipoRon against the development of albuminuria appears to occur through direct action on podocytes, independent of the systemic effects of adiponectin. Its reduction of oxidative stress confers protection against albuminuria and podocyte damage, ameliorating endothelial dysfunction in DN. Therefore, AdipoRon is a novel, promising therapeutic agent in preventing and ameliorating DN, particularly in type 2 diabetes.
Conclusion and future perspectives Despite progress in the field of pharmacologic therapies that aims to prevent or delay the progression of DN, the number of end-stage renal disease patients is rising steadily, especially in Korea [5,67]. Therefore, the development of new therapeutic agents is of crucial concern to public health. Mounting evidence suggests that AMPK activation in various tissues can help achieve metabolic homeostasis, with subsequent improvements in glucose and lipid profiles. We have summarized the role of AMPK activation in the context of several known and new activators that can treat DN by preventing renal fibrosis, extracellular matrix accumulation, apoptosis, and inflammation in the kidney (Fig. 3). However, a major pitfall in the use of AMPK activators is their as-yet-unknown adverse effects, which may counter the therapeutic effects we are aiming for. Such off-target effects involve AMPK's possible role in the stimulation of food intake through the activation of AMPK expressed in certain nuclei of the hypothalamus [68]. This provides a clear example of the need for both target and tissue specificity. Pharmacologic activation of AMPK needs to be achieved tissue specifically, and the isoforms of AMPK expressed in different tissues need to be identified [69]. In addition, we must determine the effective dose with least toxicity that can still produce detectable AMPK activation to achieve adequate metabolic regulation. The evidence of the metabolic effects of AMPK signifies just the beginning of the field, with significant challenges lying ahead in the translation of these data into feasible therapeutics for DN and obesity-related metabolic disease [5].
Conflicts of interest
Acknowledgments This study was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea funded by the Research Fund of Seoul St. Mary's Hospital, the Catholic University of Korea (C.W.P.).