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The Adiponectin Receptor Agonist Adiporon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes

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The Adiponectin Receptor Agonist Adiporon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes BASIC RESEARCH www.jasn.org The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes Yaeni Kim,1,2 Ji Hee Lim,1,3 Min Young Kim,1,3 Eun Nim Kim,1,3 Hye Eun Yoon,1,2 Seok Joon Shin,1,2 Bum Soon Choi,1,3 Yong-Soo Kim,1,3 Yoon Sik Chang,1,4 and Cheol Whee Park1,3 1Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea; 2Division of Nephrology, Department of Internal Medicine, Incheon St. Mary’s Hospital, Incheon, Korea; 3Division of Nephrology, Department of Internal Medicine, Institute for Aging and Metabolic Diseases, Seoul St. Mary’sHospital, Seoul, Korea; and 4Division of Nephrology, Department of Internal Medicine, Yeouido St. Mary’s Hospital, Seoul, Korea ABSTRACT Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor–a (PPARa) pathway through adiponectin receptors (Adi- poRs). AdipoRon is an orally active synthetic adiponectin receptor agonist. We investigated the expression of AdipoRs and the associated intracellular pathways in 27 patients withtype2diabetesandexaminedtheeffectsofAdipoRonon DNdevelopmentinmaleC57BLKS/Jdb/db mice, glomerular endothelial cells (GECs), and podocytes. The extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal function deterioration in human kidneys. Expres- sion of AdipoR1, AdipoR2, and Ca2+/calmodulin-dependent protein kinase kinase–b (CaMKKb) and numbers of phos- phorylated liver kinase B1 (LKB1)–and AMPK-positive cells significantly decreased in the glomeruli of early stage human DN. AdipoRon treatment restored diabetes-induced renal alterations in db/db mice. AdipoRon exerted renoprotective effects by directly activating intrarenal AdipoR1 and AdipoR2, which increased CaMKKb, phosphorylated Ser431LKB1, phosphorylated Thr172AMPK, and PPARa expression independently of the systemic effects of adiponectin. AdipoRon- induced improvement in diabetes-induced oxidative stress and inhibition of apoptosis in the kidneys ameliorated relevant intracellular pathways associated with lipid accumulation and endothelial dysfunction. In high-glucose–treated human GECs and murine podocytes, AdipoRon increased intracellular Ca2+ levels that activated a CaMKKb/phosphor- ylated Ser431LKB1/phosphorylated Thr172AMPK/PPARa pathway and downstream signaling, thus decreasing high- glucose–induced oxidative stress and apoptosis and improving endothelial dysfunction. AdipoRon further produced cardioprotective effects through the same pathway demonstrated in the kidney. Our results show that AdipoRon ameliorates GEC and podocyte injury by activating the intracellular Ca2+/LKB1-AMPK/PPARa pathway, suggesting its efficacy for treating type 2 diabetes–associated DN. J Am Soc Nephrol 29: 1108–1127, 2018. doi: https://doi.org/10.1681/ASN.2017060627 Received June 8, 2017. Accepted December 7, 2017. Although diabetic nephropathy (DN) is tradi- tionally characterized by hyperglycemia-induced Published online ahead of print. Publication date available at www.jasn.org. metabolic and hemodynamic changes, accumu- lating evidences suggest that derangements in Correspondence: Dr. Cheol Whee Park, Division of Nephrology, lipid metabolism play a crucial role in DN devel- Department of Internal Medicine, Seoul St. Mary’sHospital, College of Medicine, The Catholic University of Korea, 222, opment and progression. Accumulation of free Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea. fatty acids, which are otherwise used as an energy Email: [email protected] source, in tubular epithelial cells of diabetic kid- Copyright © 2018 by the American Society of Nephrology neys indicates a state of energy surplus.1 This state 1108 ISSN : 1046-6673/2904-1108 JAmSocNephrol29: 1108–1127, 2018 www.jasn.org BASIC RESEARCH of energy surplus (referred to as lipotoxicity) is character- Significance Statement ized by the deposition of fatty acid metabolites such as diacylglycerols and ceramides in nonadipose organs Adiponectin is an adipokine secreted by adipocytes known to exert favor- and leads to toxicity and cell death.2 Although mainstream able effects in the milieu of diabetic and metabolic syndrome through its anti- fl fi research indicates that slowdown of fatty acid b-oxidation in ammatory, anti brotic, and antioxidant effects. In human and animal diabetic nephropathy, the expression of adiponectin receptors is reduced. 3 leads to the accumulation of different lipid products, This manuscript reveals a favorable effect of AdipoRon, an orally active emerging evidence indicates that rapid but incomplete synthetic adiponectin receptor agonist, in protection, even reversal, of di- b-oxidation in the nonadipose tissue and by-products of abeticnephropathyproducedbythe activationof adiponectinreceptors and ++ oxidative stress promote the formation of toxic lipid inter- downstream targets through increased intracellular Ca /AMPK-LKB1/ mediates.4 PPARa pathway. AdipoRon may be a promising drug for restoration of diabetic nephropathyintype2diabetes. Adiponectin is one of the numerous adipokines secreted by adipocytes.5 It exerts favorable effects in the milieu of metabolic syndrome through anti-inflammatory, antifi- RESULTS brotic, and antioxidant effects.6 Adiponectin mediates fatty acid metabolism by inducing AMP-activated protein Human Diabetic Kidneys Show Decreased kinase (AMPK) phosphorylation and increasing peroxi- Intraglomerular AdipoR1/AdipoR2 Expression and some proliferative-activated receptor–a (PPARa)expres- Decreased CaMKKb/Phosphorylated Ser431LKB1/ sion, which in turn upregulate the expression of acyl CoA Phosphorylated Thr172AMPK/PPARa Pathway oxidase and uncoupling proteins involved in energy con- The patient group included 27 patients with biopsy-proven DN. sumption.7,8 Low circulating adiponectin levels in obese Clinical characteristics of these patients are shown (Supplemental patients with a risk of insulin resistance, type 2 diabetes, Table 1). Nondiabetic subjects included healthy controls (n=6) and cardiovascular disease9 and increased adiponectin ex- with minor urinary abnormalities. In diabetes, the extent of glo- pression in state of albuminuria indicate the protective and merulosclerosis and tubulointerstitial fibrosis markedly increased compensatory role of adiponectin10 to mitigate further with renal function deterioration (Figure 1, A and B). Immuno- renal injury against the development of overt nephropa- fluorescence analysis showed that AdipoR1/AdipoR2, CaMKKb, thy.5,11 These beneficial effects of adiponectin have promp- andnephrinexpressionandphosphorylatedAMPK-andphos- ted research on drugs that mimic adiponectin, yet this phorylated LKB1-positive cell number significantly decreased in manner of increasing the level of circulating adiponectin the glomerulus of human diabetic kidneys compared with that of is not a panacea. Moreover, adiponectin overexpression is nondiabetic control kidneys even in the earliest CKD stage. There associated with adverse effects such as reduced bone den- were no significant differences in the expression of AdipoRs and sity, left ventricular hypertrophy, weight gain, tumor their relevant downstream molecules with increasing stages of growth, and infertility.12–14 Therefore, there is a need to CKD (Figure 1, C–L) and in those with or without angiotensin develop a novel agent that could deliver the favorable ef- II receptor blocker use in the kidneys (Supplemental Figure 1). fects of adiponectin but not the detrimental pitfalls due to adiponectin excess. AdipoRon Improves Renal Function without Affecting AdipoRon is an orally active synthetic adiponectin receptor Serum Adiponectin and Glucose Levels in db/db Mice agonist developed by Okada-Iwabu et al.15 In db/db Serum adiponectin level was higher in nondiabetic mice than in di- mice, AdipoRon binds to AdipoRs AdipoR1 and AdipoR2 abetic mice. AdipoRon treatment did not affect body weight or food to activate AMPK and PPARa, respectively, and induces intake. Moreover, it did not affect plasma glucose, HbA1c, and serum such prometabolic effects as improved insulin sensitivity, creatinine levels in both nondiabetic and diabetic mice. There were no weight neutrality, and expanded life span.15 Diminished adi- differences in systolic BP among study groups and creatinine clearance ponectin-associated metabolic effect in AdipoR1-/AdipoR2- decreased in db/db mice treated with AdipoRon. Moreover, albumin- knockout mice and restoration of obesity-induced metabolic uria, urinary nitric oxide metabolites (NOx), and homeostatic model alterations in high-fat-diet–fed mice by AdipoRon adminis- assessment–insulin resistance (HOMA-IR) index improved in db/db tration with implication on fatty acid combustion suggest that mice treated with AdipoRon compared with those in db/db control AdipoRon is a promising agent for treating type 2 diabe- andindiabeticmicebeforethetreatment(Table1).Theseresults tes.15,16 This instigated us to investigate the favorable effects suggest that AdipoRon ameliorates metabolic and renal function pa- of AdipoRon against DN in db/db mice, human glomerular rameters independently of serum adiponectin and glucose levels. endothelial cells (GECs), and murine podocytes. In addition, we examined renal AdipoR1/AdipoR2 expression and AdipoRon Activates the CaMKKb/Phosphorylated Ser CaMKKb/phosphorylated Ser431LKB1/phosphorylated Thr172 431LKB1/Phosphorylated Thr172AMPK/PPARa Pathway
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