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

Kim, Yaeni; Lim, Ji Hee; Kim, Min Young; Kim, Eun Nim; Yoon, Hye Eun; Shin, Seok Joon; Choi, Bum Soon; Kim, Yong‐Soo; Chang, Yoon Sik; Park, Cheol Whee

doi:10.1681/asn.2017060627

Cited by 154 publications

(140 citation statements)

References 40 publications

(48 reference statements)

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“…ADIPOR2, encoding adiponectin receptor2, has been implicated in cardiovascular diseases [40,41], fatty liver disease [42], diabetes [43], diabetic nephropathy [44], and bone metabolic disorders [45]. In each of these pathogenic conditions forced overexpression of ADIPOR2 ameliorates the disease process.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of miR-19a protects neurons against ischemic stroke through modulating glucose metabolism and neuronal apoptosis

Wang

Liu

et al. 2019

Cell Mol Biol Lett

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Background: Accumulating evidence has shown that altered microRNA (miR) modulation is implicated in the pathologies of ischemic stroke. However, it is unclear whether and how hsa-miR-19a-3p mediates cerebral ischemic injury. Herein, we investigated the functional role of miR-19a-3p in cerebral ischemic injury and explored its underlying regulatory mechanism. Methods: In vivo ischemic/reperfusion (I/R) neuronal injury and in vitro oxygenglucose deprivation (OGD) were established. Expression of miR-19a-3p was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Glucose uptake, lactate production, and apoptosis were determined. ADIPOR2 was predicted as a target of miR-19a-3p in silico and experimentally validated by qRT-PCR, Western blot analysis and luciferase assay assays. Results: MiR-19a expression was significantly downregulated and upregulated in rat neurons and astrocytes, respectively (P < 0.01). A significantly elevated level of miR-19a-3p was found in I/R and OGD models in comparison to sham/control groups (P < 0.01). Expression of the glycolysis enzyme markers LDHA, PKM2, HK2, Glut1 and PDK1, apoptosis-related factors levels, apoptosis, glucose uptake, and lactate production were significantly repressed by both I/R and OGD (P < 0.01 in each case). Moreover, miR-19a-3p mimic aggravated, while miR-19a-3p inhibitor alleviated, the above observations. Adipor2 was predicted and confirmed to be a direct target of miR-19a. Furthermore, restoration of Adipor2 reversed miR-19a-3p-induced effects. Conclusions: Collectively, our results indicate that elevated miR-19a-3p mediates cerebral ischemic injury by targeting ADIPOR2. MiR-19a-3p attenuation thus might offer hope of a novel therapeutic target for ischemic stroke injury treatment.

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Section: Discussionmentioning

confidence: 99%

Inhibition of miR-19a protects neurons against ischemic stroke through modulating glucose metabolism and neuronal apoptosis

Wang

Liu

et al. 2019

Cell Mol Biol Lett

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“…AdipoRON effectively improved insulin sensitivity and restored glucose homeostasis via the activation of AdipoR1-AMPK-PGC1α and AdipoR2-PPARα signaling pathways (162). AdipoRON treatment also mimicked adiponectin's established anti-diabetic effects (163) and ability to enhance cellular capacity for mitigating oxidative-stress (162,164), enhancing lipid/glucose oxidation in mitochondria (162,164), anti-inflammatory responses (162,(164)(165)(166)(167), lifeprolonging effect (162,163), anti-cancer effects (168,169), procell survival and anti-apoptotic effect (170,171), neuronal- (172,173), reno- (174,175), and cardio-/vascular-protective effects (165,(176)(177)(178)(179). However, exciting AdipoRON research in animal models has not been translated to establishment of a drug for human use and the search continues for additional small molecule AdipoR agonists which have little or no toxicity.…”

Section: Adiporonmentioning

confidence: 97%

Examining the Potential of Developing and Implementing Use of Adiponectin-Targeted Therapeutics for Metabolic and Cardiovascular Diseases

Liu¹,

Sweeney

2019

Front. Endocrinol.

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Cardiometabolic diseases encompass those affecting the heart and vasculature as well as other metabolic problems, such as insulin resistance, diabetes, and non-alcoholic fatty liver disease. These diseases tend to have common risk factors, one of which is impaired adiponectin action. This may be due to reduced bioavailability of the hormone or resistance to its effects on target tissues. A strong negative correlation between adiponectin levels and cardiometabolic diseases has been well-documented and research shown that adiponectin has cardioprotective, insulin sensitizing and direct beneficial metabolic effects. Thus, therapeutic approaches to enhance adiponectin action are widely considered to be desirable. The complexity of adiponectin structure and function has so far made progress in this area less than ideal. In this article we will review the effects and mechanism of action of adiponectin on cardiometabolic tissues, identify scenarios where enhancing adiponectin action would be of clinical value and finally discuss approaches via which this can be achieved.

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“…AdipoRon reduced sphingolipids levels, which are closely related to lipotoxicity, inflammation and insulin resistance [189]. Moreover, AdipoRon ameliorated renal alterations in db/db mice by reducing oxidative stress and apoptosis in the kidney [190].…”

Section: Adiponectin Receptor Agonistsmentioning

confidence: 98%

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Opazo-Ríos

Mas

Marín-Royo

et al. 2020

IJMS

190

147

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Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.

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

Cited by 154 publications

References 40 publications

Inhibition of miR-19a protects neurons against ischemic stroke through modulating glucose metabolism and neuronal apoptosis

Inhibition of miR-19a protects neurons against ischemic stroke through modulating glucose metabolism and neuronal apoptosis

Examining the Potential of Developing and Implementing Use of Adiponectin-Targeted Therapeutics for Metabolic and Cardiovascular Diseases

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

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