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 American Society of Nephrology 2018 Journal of the American Society of Nephrology Vol.29 No.4

Blood Pressure Control in Patients with Diabetic Kidney Disease

( Yaeni Kim ),( Won Kim ),( Jwa-kyung Kim ),( Ju Young Moon ),( Samel Park ),( Cheol Whee Park ),( Hoon Suk Park ),( Sang Heon Song ),( Tae-hyun Yoo ),( So-young Lee ),( Eun Young Lee ),( Jeonghwan Le 대한전해질학회 2022 Electrolytes & Blood Pressure Vol.20 No.2

Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease. Blood pressure (BP) control can reduce the risks of cardiovascular (CV) morbidity, mortality, and kidney disease progression. Recently, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines have suggested the implementation of a more intensive BP control with a target systolic BP (SBP) of <120mmHg based on the evidence that the CV benefits obtained is outweighed by the kidney injury risk associated with a lower BP target. However, an extremely low BP level may paradoxically aggravate renal function and CV outcomes. Herein, we aimed to review the existing literature regarding optimal BP control using medications for DKD.

The protective effect of resveratrol on vascular aging by modulation of the renin–angiotensin system

Kim, Eun Nim,Kim, Min Young,Lim, Ji Hee,Kim, Yaeni,Shin, Seok Joon,Park, Cheol Whee,Kim, Yong-Soo,Chang, Yoon Sik,Yoon, Hye Eun,Choi, Bum Soon Elsevier Scientific Publ. Co 2018 Atherosclerosis Vol.270 No.-

<P><B>Abstract</B></P> <P><B>Background and aims</B></P> <P>This study evaluated the effects of resveratrol on arterial aging and the renin–angiotensin system (RAS) in mice and vascular smooth muscle cells (VSMCs).</P> <P><B>Methods</B></P> <P>Aging mice were divided into control and resveratrol groups. Histological changes, inflammation, oxidative stress, RAS components, and the expression of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1), peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α), and anti-oxidative enzymes was measured in thoracic aortas of 24-month-old mice. The effect of resveratrol on fibrosis, cell senescence, and RAS components was also investigated in VSMCs stimulated by angiotensin (Ang) II.</P> <P><B>Results</B></P> <P>Aorta media thickness, inflammation, fibrosis, and oxidative stress were significantly lower in the resveratrol group than in the control group. Resveratrol treatment decreased serum Ang II level and the aortic expression of prorenin receptor (PRR) and angiotensin converting enzyme (ACE), and increased serum Ang-(1–7) level and the expression of ACE2, Ang II type 2 receptor (AT2R), and Mas receptor (MasR). Resveratrol increased the expression of phosphorylated AMPK, SIRT1, PGC-1α, phosphorylated endothelial nitric oxide synthase and superoxide dismutase 1 and 2, and decreased that of NADPH oxidase 2 and 4. In Ang II-stimulated VSMCs, resveratrol treatment markedly decreased the number of senescence associated β-galactosidase stained cells and pro-fibrotic protein expression and increased the expression of AT2R and MasR.</P> <P><B>Conclusions</B></P> <P>Resveratrol protects against arterial aging and this effect is associated with reduced activity of the PRR–ACE–Ang II axis and stimulation of the ACE2–Ang-(1–7)–ATR2–MasR axis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Resveratrol protected against arterial aging by attenuating inflammation and oxidative stress. </LI> <LI> Resveratrol reduced the activity of the prorenin receptor-angiotensin converting enzyme-angiotensin II axis in aorta of aging mice. </LI> <LI> Resveratrol stimulated the activity of the angiotensin converting enzyme 2-angiotensin-(1–7)-angiotensin II type 2 receptor-Mas receptor axis both<I>in vivo</I> and <I>in vitro</I>. </LI> </UL> </P>

Adiponectin receptor agonist AdipoRon decreased ceramide, and lipotoxicity, and ameliorated diabetic nephropathy

Choi, Sun Ryoung,Lim, Ji Hee,Kim, Min Young,Kim, Eun Nim,Kim, Yaeni,Choi, Beom Soon,Kim, Yong-Soo,Kim, Hye Won,Lim, Kyung-Min,Kim, Min Jeong,Park, Cheol Whee Elsevier 2018 clinical and experimental Vol.85 No.-

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Adiponectin is known to take part in the regulation of energy metabolism. AdipoRon, an orally-active synthetic adiponectin agonist, binds to both adiponectin receptors (AdipoR)1/R2 and ameliorates diabetic complications. Among the lipid metabolites, the ceramide subspecies of sphingolipids have been linked to features of lipotoxicity, including inflammation, cell death, and insulin resistance. We investigated the role of AdipoRon in the prevention and development of type 2 diabetic nephropathy.</P> <P><B>Methods</B></P> <P>AdipoRon (30 mg/kg) was mixed into the standard chow diet and provided to <I>db/db</I> mice (<I>db</I> + AdipoRon, <I>n</I> = 8) and age-matched male <I>db/m</I> mice (<I>dm</I> + AdipoRon, <I>n</I> = 8) from 17 weeks of age for 4 weeks. Control <I>db/db</I> (<I>db</I> cont, <I>n</I> = 8) and <I>db/m</I> mice (<I>dm</I> cont, <I>n</I> = 8) were fed a normal diet of mouse chow.</P> <P><B>Results</B></P> <P>AdipoRon-fed <I>db/db</I> mice showed a decreased amount of albuminuria and lipid accumulation in the kidney with no significant changes in serum adiponectin, glucose, and body weight. Restoring expression of adiponectin receptor-1 and -2 in the renal cortex was observed in <I>db/db</I> mice with AdipoRon administration. Consistent up-regulation of phospho-Thr<SUP>172</SUP> AMP-dependent kinase (AMPK), peroxisome proliferative-activated receptor α (PPARα), phospho-Thr<SUP>473</SUP> Akt, phospho-Ser<SUP>79</SUP>Acetyl-CoA carboxylase (ACC), and phospho-Ser<SUP>1177</SUP> endothelial NO synthase (eNOS), and down-regulation of protein phosphatase 2A (PP2A), sterol regulatory element-binding protein-1c (SREBP-1c), and inducible nitric oxide synthase (iNOS) were associated within the same group. AdipoRon lowered cellular ceramide levels by activation of acid ceramidase, which normalized ceramide to sphingosine-1 phosphate (S1P) ratio. In glomerular endothelial cells (GECs) and podocytes, AdipoRon treatment markedly decreased palmitate-induced lipotoxicity, which ultimately ameliorated oxidative stress and apoptosis.</P> <P><B>Conclusions</B></P> <P>AdipoRon may prevent lipotoxicity in the kidney particularly in both GECs and podocytes through an improvement in lipid metabolism, as shown by the ratio of ceramide to sphingosines, and further contribute to prevent deterioration of renal function, independent of the systemic effects of adiponectin. The reduction in oxidative stress and apoptosis by AdipoRon provides protection against renal damage, thereby ameliorating endothelial dysfunction in type 2 diabetic nephropathy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Superfluous ceramide via decrease in acid ceramidase activity causes lipotoxicity. </LI> <LI> Adiponectin and adiponectin receptors potentially increase ceramidase activity. </LI> <LI> AdipoRon ameliorated renal lipotoxicity by AdipoR1-AMPK and AdipoR2-PPARα pathway. </LI> <LI> AdipoRon is a promising tool for treatment of diabetic nephropathy in type 2 DM. </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

Extracellular Superoxide Dismutase Attenuates Renal Oxidative Stress Through the Activation of Adenosine Monophosphate-Activated Protein Kinase in Diabetic Nephropathy

Hong, Yu Ah,Lim, Ji Hee,Kim, Min Young,Kim, Yaeni,Park, Hoon Suk,Kim, Hyung Wook,Choi, Bum Soon,Chang, Yoon Sik,Kim, Hye Won,Kim, Tae-Yoon,Park, Cheol Whee Mary Ann Liebert 2017 ANTIOXIDANTS AND REDOX SIGNALING Vol. No.

Baseline characteristics of the autosomal‐dominant polycystic kidney disease sub‐cohort of the KoreaN cohort study for outcomes in patients with chronic kidney disease

Kim, Hyunsuk,Koh, Junga,Park, Sue K,Oh, Kook H,Kim, Yeong H,Kim, Yaeni,Ahn, Curie,Oh, Yun K John Wiley Sons Australia, Ltd 2019 Nephrology Vol.24 No.4

<P><B>ABSTRACT</B></P><P><B>Aim</B></P><P>The aim of this study was to describe the baseline characteristics of autosomal‐dominant polycystic kidney disease (ADPKD) in a cohort of Korean patients with chronic kidney disease (CKD).</P><P><B>Methods</B></P><P>From April 2011 to February 2016, patients with CKD stage 1–5 (pre‐dialysis) were enrolled as an ADPKD sub‐cohort of the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease. Baseline characteristics, the correlation of kidney and liver volume and kidney function and the factors associated with kidney function were analysed.</P><P><B>Results</B></P><P>A total of 364 ADPKD patients with a mean estimated glomerular filtration rate (eGFR) of 68.1 ± 33.3 mL/min per 1.73 m<SUP>2</SUP> (50.5% male with a mean age of 47.0 ± 10.6 years) were enrolled from nine hospitals in Korea. Initially, 55.8% of the patients were asymptomatic, and pain was the most common symptom (12.9%); 87.6 and 77.5% of the patients had hypertension and hepatic cysts, respectively. The height‐adjusted total kidney volumes (htTKV) were higher in male patients than in female patients. In contrast, the height‐adjusted total liver volumes were higher in female patients than in male patients. The decrease rate of eGFR depending on Log(htTKV) was larger in the group aged between 41 and 50 years than the other age groups. Older age, a higher 24‐h urine protein excretion, larger htTKV and hyperuricemia were independently associated with lower eGFR, whereas using febuxostat was independently associated with higher eGFR.</P><P><B>Conclusion</B></P><P>This sub‐cohort will provide clinical characteristics and outcomes of Korean ADPKD patients, which can be compared with those of other previous cohorts. We have identified factors associated with advanced‐stage CKD in Korean patients with ADPKD.</P><P><B>Summary at a Glance</B></P><P>This paper describes the clinical characteristics and outcomes of an underreported cohort of patients, namely, ethnic Koreans with ADPKD. Older age, proteinuria, larger height‐adjusted total kidney volume and hyperuricemia were independently associated with lower eGFR.</P>

Retinopathy and left ventricular hypertrophy in patients with chronic kidney disease: Interrelationship and impact on clinical outcomes

Kim, Yaeni,Cho, Jung Sun,Cho, Won-kyung,Yoon, Hye Eun,Hong, Yu Ah,Chang, Yoon Kyung,Yang, Chul Woo,Kim, Suk Young,Hwang, Hyeon Seok Elsevier 2017 INTERNATIONAL JOURNAL OF CARDIOLOGY Vol.249 No.-

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Retinopathy and left ventricular hypertrophy (LVH) are representative markers of microvascular and cardiac dysfunction in patients with chronic kidney disease (CKD). However, their relationship and their combined effects on clinical outcomes are unknown.</P> <P><B>Methods</B></P> <P>We included 401 patients with nondialysis-dependent CKD stage 3–5 who had been examined with fundus photography for diabetic or hypertensive retinopathy. The presence of LVH was identified by echocardiography. The clinical significance of retinopathy and LVH was evaluated in terms of the rate of renal function decline and for any cardiovascular event (CVE)/death.</P> <P><B>Results</B></P> <P>CKD patients with retinopathy had a higher prevalence of LVH than those without retinopathy (38.9% vs. 27.6%, <I>P</I> =0.017). The presence of retinopathy was independently associated with LVH (odds ratio 1.69, 95% confidence interval [CI] 1.02, 2.80). Compared with subjects without either retinopathy or LVH, the coexistence of retinopathy and LVH was independently associated with rapid renal function decline (β=−3.28; 95% CI −6.52, −0.04), whereas retinopathy or LVH alone were not. Patients with both retinopathy and LVH had a higher risk of CVE/death (adjusted hazard ratio 2.75; 95% CI 1.44, 5.26) than patients with either factor alone. A significant synergistic interaction was observed between retinopathy and LVH to predict CVE/death (<I>P</I> for interaction=0.049).</P> <P><B>Conclusions</B></P> <P>Retinopathy was independently associated with LVH. The coexistence of retinopathy and LVH was associated with higher risks of CKD progression and CVE/death than was either factor alone, and their combined effects synergized to predict the risk of CVE/death.</P>

Can management of the components of metabolic syndrome modify the course of chronic kidney disease?

( Yaeni Kim ),( Cheol Whee Park ) 대한신장학회 2020 Kidney Research and Clinical Practice Vol.39 No.2

New therapeutic agents in diabetic nephropathy

( Yaeni Kim ),( Cheol Whee Park ) 대한내과학회 2017 The Korean Journal of Internal Medicine Vol.32 No.1

Studies investigating diabetic nephropathy (DN) have mostly focused on interpreting the pathologic molecular mechanisms of DN, which may provide valuable tools for early diagnosis and prevention of disease onset and progression. Currently, there are few therapeutic drugs for DN, which mainly consist of antihypertensive and antiproteinuric measures that arise from strict renin-angiotensin-aldosterone system inactivation. However, these traditional therapies are suboptimal and there is a clear, unmet need for treatments that offer effective schemes beyond glucose control. The complexity and heterogeneity of the DN entity, along with ambiguous renal endpoints that may deter accurate appraisal of new drug potency, contribute to a worsening of the situation. To address these issues, current research into original therapies to treat DN is focusing on the intrinsic renal pathways that intervene with intracellular signaling of anti-inflammatory, antifibrotic, and metabolic pathways. Mounting evidence in support of the favorable metabolic effects of these novel agents with respect to the renal aspects of DN supports the likelihood of systemic beneficial effects as well. Thus, when translated into clinical use, these novel agents would also address the comorbid factors associated with diabetes, such as obesity and risk of cardiovascular disease. This review will provide a discussion of the promising and effective therapeutic agents for the management of DN.

Adenosine monophosphateeactivated protein kinase in diabetic nephropathy

( Yaeni Kim ),( Cheol Whee Park ) 대한신장학회 2016 Kidney Research and Clinical Practice Vol.35 No.2

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and its pathogenesis is complex and has not yet been fully elucidated. Abnormal glucose and lipid metabolism is key to understanding the pathogenesis of DN, which can develop in both type 1 and type 2 diabetes. A hallmark of this disease is the accumulation of glucose and lipids in renal cells, resulting in oxidative and endoplasmic reticulum stress, intracellular hypoxia, and inflammation, eventually leading to glomerulosclerosis and interstitial fibrosis. There is a growing body of evidence demonstrating that dysregulation of 5′ adenosine monophosphateeactivated protein kinase (AMPK), an enzyme that plays a principal role in cell growth and cellular energy homeostasis, in relevant tissues is a key component of the development of metabolic syndrome and type 2 diabetes mellitus; thus, targeting this enzyme may ameliorate some pathologic features of this disease. AMPK regulates the coordination of anabolic processes, with its activation proven to improve glucose and lipid homeostasis in insulin-resistant animal models, as well as demonstrating mitochondrial biogenesis and antitumor activity. In this review, we discuss new findings regarding the role of AMPK in the pathogenesis of DN and offer suggestions for feasible clinical use and future studies of the role of AMPK activators in this disorder.