Yaeni Kim

Fenofibrate Improves Renal Lipotoxicity through Activation of AMPK-PGC-1α in db/db Mice

Peroxisome proliferator-activated receptor (PPAR)-α, a lipid-sensing transcriptional factor, serves an important role in lipotoxicity. We evaluated whether fenofibrate has a renoprotective effect by ameliorating lipotoxicity in the kidney. Eight-week-old male C57BLKS/J db/m control and db/db mice, divided into four groups, received fenofibrate for 12 weeks. In db/db mice, fenofibrate ameliorated albuminuria, mesangial area expansion and inflammatory cell infiltration. Fenofibrate inhibited accumulation of intra-renal free fatty acids and triglycerides related to increases in PPARα expression, phosphorylation of AMP-activated protein kinase (AMPK), and activation of Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-estrogen-related receptor (ERR)-1α-phosphorylated acetyl-CoA carboxylase (pACC), and suppression of sterol regulatory element-binding protein (SREBP)-1 and carbohydrate regulatory element-binding protein (ChREBP)-1, key downstream effectors of lipid metabolism. Fenofibrate decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and FoxO3a phosphorylation in kidneys, increasing the B cell leukaemia/lymphoma 2 (BCL-2)/BCL-2-associated X protein (BAX) ratio and superoxide dismutase (SOD) 1 levels. Consequently, fenofibrate recovered from renal apoptosis and oxidative stress, as reflected by 24 hr urinary 8-isoprostane. In cultured mesangial cells, fenofibrate prevented high glucose-induced apoptosis and oxidative stress through phosphorylation of AMPK, activation of PGC-1α-ERR-1α, and suppression of SREBP-1 and ChREBP-1. Our results suggest that fenofibrate improves lipotoxicity via activation of AMPK-PGC-1α-ERR-1α-FoxO3a signaling, showing its potential as a therapeutic modality for diabetic nephropathy.

Color vision in Parkinson’s disease and essential tremor

Background and purpose:  Decreased visual function is one of the non‐motor dysfunctions of Parkinson’s disease (PD). Recent evidences suggest that essential tremor (ET) is not ‘pure’ motor disorder and there is growing evidence that this disease is a multiple‐system disorder. In some cases, it is difficult to differentiate ET from PD. In addition, there is considerable controversy regarding the relationship between PD and ET. The objective of this study was to compare color discrimination dysfunction amongst patients with PD and ET and to investigate the clinical relevance.

Vascular endothelial growth factor-receptor 1 inhibition aggravates diabetic nephropathy through eNOS signaling pathway in db/db mice.

The manipulation of vascular endothelial growth factor (VEGF)-receptors (VEGFRs) in diabetic nephropathy is as controversial as issue as ever. It is known to be VEGF-A and VEGFR2 that regulate most of the cellular actions of VEGF in experimental diabetic nephropathy. On the other hand, such factors as VEGF-A, -B and placenta growth factor bind to VEGFR1 with high affinity. Such notion instigated us to investigate on whether selective VEGFR1 inhibition with GNQWFI hexamer aggravates the progression of diabetic nephropathy in db/db mice. While diabetes suppressed VEGFR1, it did increase VEGFR2 expressions in the glomerulus. Db/db mice with VEGFR1 inhibition showed more prominent features with respect to, albuminuria, mesangial matrix expansion, inflammatory cell infiltration and greater numbers of apoptotic cells in the glomerulus, and oxidative stress than that of control db/db mice. All these changes were related to the suppression of diabetes-induced increases in PI3K activity and Akt phosphorylation as well as the aggravation of endothelial dysfunction associated with the inactivation of FoxO3a and eNOS-NOx. In cultured human glomerular endothelial cells (HGECs), high-glucose media with VEGFR1 inhibition induced more apoptotic cells and oxidative stress than did high-glucose media alone, which were associated with the suppression of PI3K-Akt phosphorylation, independently of the activation of AMP-activated protein kinase, and inactivation of FoxO3a and eNOS-NOx pathway. In addition, transfection with VEGFR1 siRNA in HGECs also suppressed PI3K-Akt-eNOS signaling. In conclusion, the specific blockade of VEGFR1 with GNQWFI caused severe renal injury related to profound suppression of the PI3K-Akt, FoxO3a and eNOS-NOx pathway, giving rise to the oxidative stress-induced apoptosis of glomerular cells in type 2 diabetic nephropathy.

Clinical outcome of kidney transplantation from deceased donors with acute kidney injury by Acute Kidney Injury Network criteria

PURPOSE In this study, we investigated the outcome of kidney transplantation (KT) from deceased donors with acute kidney injury (AKI), as defined by the Acute Kidney Injury Network criteria. METHODS Of 156 deceased donors, kidneys from 43 donors (27.6%) with AKI were transplanted into 57 recipients (AKI group). Another 147 recipients received kidneys from donors without AKI (non-AKI group). We compared the incidence of delayed graft function, allograft function for 1 year after KT, and long-term (5 and 10 years) graft survival rate between the 2 groups. RESULTS Delayed graft function developed more frequently in the AKI group than in the non-AKI group (42.1% vs 12.2%; P<.05), and allograft function-assessed by the modification of diet in renal disease equation-showed a significantly deteriorating pattern at 2 weeks and 1, 3, and 6 months after KT compared with that in the non-AKI group (P<.05 for comparisons at each time point). However, allograft function at 12 months after KT and the long-term allograft and patient survival rates did not differ between the AKI and non-AKI groups. CONCLUSIONS In KT from deceased donors, the AKI group that received kidneys with AKI, as defined by the Acute Kidney Injury Network criteria, showed a higher delayed graft function rate and lower allograft function for 6 months after KT but no effect on allograft function 1 year after KT and on long-term allograft survival.

Clinical outcome in patients with chronic antibody-mediated rejection treated with and without rituximab and intravenous immunoglobulin combination therapy.

We previously reported that rituximab (RTX) and intravenous immunoglobulin (IVIg) combination therapy (RIT) is effective in treating patients with chronic active antibody-mediated rejection (CAMR), and the proteinuria level can determine the response to RIT. However, the results were not compared to those of patients who did not receive RIT. Fifty-nine patients with CAMR were divided into 2 groups: an RIT treated group (n = 25) and a historic control (HC) group who had not received RIT (n = 29). The RIT group was treated with RTX (375 mg/m(2)) and IVIg (0.4 g/kg) for 4 days. We compared the decline in glomerular filtration rate/month (ΔeGFR), RIT-related complications, and allograft survival rate in both groups. We also compared the allograft survival rate between patients with high proteinuria (spot urine protein/creatinine [PC] ratio > 3.5 g/g) and low proteinuria (PC ratio < 3.5 g/g). ΔeGFR was significantly decreased in the RIT group compared with the HC group after 6 months (P < 0.05). No serious complications were associated with RIT, and only one case of herpes zoster infection developed. The overall allograft survival rate in the RIT group was significantly higher than in the HC group. In both groups, patients with low proteinuria survived better than patients with heavy proteinuria (P < 0.05). The allograft survival rate was greater in the high proteinuria RIT group than that in the HC group. RIT treatment is recommended for delaying the progression of CAMR without serious complications, and is not limited by the presence of heavy proteinuria.

Adenosine monophosphate–activated protein kinase in diabetic nephropathy

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 monophosphate–activated 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.

New therapeutic agents in diabetic nephropathy

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.

De novo glomerulitis associated with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: A single-center experience

Background Nephrotic syndrome (NS) and proteinuria are uncommon, often unrecognized manifestations of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). Only a few isolated case reports and case series involving smaller number of patients who developed NS after HSCT have been published. Methods We reviewed the renal histopathological examination findings and clinical records of 15 patients who developed proteinuria after HSCT at Seoul and Yeouido St. Mary′s Hospital (Seoul, Korea). We also measured the anti-PLA2R antibodies (M-type phospholipase A2 receptor) in the serum samples from the seven patients at the time of renal biopsy. Results All patients had GVHD. The most common indication for biopsy was proteinuria (>1 g/day), with nine patients having nephrotic range proteinuria. The most common histopathological finding was membranous nephropathy (MN; n = 12). Other findings were membranoproliferative glomerulonephritis, C1q nephropathy, and diabetic nephropathy. Eleven patients were treated with immunosuppressive agents, and three patients were treated only with angiotensin II receptor blocker. The overall response rate, including complete remission (urinary protein level <0.3 g/day) and partial remission (urinary protein level = 0.31–3.4 g/day), was 73%. The mean follow-up period was 26 months, and none of the patients developed end-stage renal disease. All of the seven patients with MN had negative findings for anti-PLA2R antibodies, measured using an enzyme-linked immunosorbent assay kit. Conclusion In this study the findings of 15 renal biopsies were analyzed and to our knowledge this is the largest clinicopathological study of GVHD-related biopsy-proven nephropathy. Approximately 80% of the patients were MN and 73% responded either partially or completely to immunosuppressive treatment. Currently, there is an increase in the incidence of GVHD-mediated renal disease, and therefore, renal biopsy is essential for diagnosing the nephropathy and preventing the progression of renal disease.

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

BACKGROUND 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. METHODS AdipoRon (30 mg/kg) was mixed into the standard chow diet and provided to db/db mice (db + AdipoRon, n = 8) and age-matched male db/m mice (dm + AdipoRon, n = 8) from 17 weeks of age for 4 weeks. Control db/db (db cont, n = 8) and db/m mice (dm cont, n = 8) were fed a normal diet of mouse chow. RESULTS AdipoRon-fed db/db 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 db/db mice with AdipoRon administration. Consistent up-regulation of phospho-Thr172 AMP-dependent kinase (AMPK), peroxisome proliferative-activated receptor α (PPARα), phospho-Thr473 Akt, phospho-Ser79Acetyl-CoA carboxylase (ACC), and phospho-Ser1177 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. CONCLUSIONS 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.

Cinacalcet-mediated activation of the CaMKKβ-LKB1-AMPK pathway attenuates diabetic nephropathy in db/db mice by modulation of apoptosis and autophagy

Apoptosis and autophagy are harmoniously regulated biological processes for maintaining tissue homeostasis. AMP-activated protein kinase (AMPK) functions as a metabolic sensor to coordinate cellular survival and function in various organs, including the kidney. We investigated the renoprotective effects of cinacalcet in high-glucose treated human glomerular endothelial cells (HGECs), murine podocytes and C57BLKS/J-db/db mice. In cultured HGECs and podocytes, cinacalcet decreased oxidative stress and apoptosis and increased autophagy that were attributed to the increment of intracellular Ca2+ concentration and the phosphorylation of Ca2+/calmodulin-dependent protein kinase kinaseβ (CaMKKβ)-Liver kinase B1 (LKB1)-AMPK and their downstream signals including the phosphorylation of endothelial nitric oxide synthase (eNOS) and increases in superoxide dismutases and B cell leukemia/lymphoma 2/BCL-2-associated X protein expression. Interestingly, intracellular chelator BAPTA-AM reversed cinacalcet-induced CaMKKβ elevation and LKB1 phosphorylation. Cinacalcet reduced albuminuria without influencing either blood glucose or Ca2+ concentration and ameliorated diabetes-induced renal damage, which were related to the increased expression of calcium-sensing receptor and the phosphorylation of CaMKKβ-LKB1. Subsequent activation of AMPK was followed by the activation of peroxisome proliferator-activated receptor γ coactivator-1α and phospho-Ser1177eNOS-nitric oxide, resulting in a decrease in apoptosis and oxidative stress as well as an increase in autophagy.Our results suggest that cinacalcet increases intracellular Ca2+ followed by an activation of CaMKKβ-LKB1-AMPK signaling in GECs and podocytes in the kidney, which provides a novel therapeutic means for type 2 diabetic nephropathy by modulation of apoptosis and autophagy.