A novel allocation scheme for deceased donor kidneys to balance equity and utility.

Background: Patients with sensitization and blood type O experience increased waiting times for deceased-donor kidney transplantation (DDKT). While allocation benefits are needed to resolve inequity in DDKT opportunity, whether DDKT has comparable outcomes in this disadvantaged population requires further study. This study assessed these outcomes and developed a new allocation system that balances equity and utility. Methods: Patients from national and hospital cohorts from two centers in Korea were categorized as B1 to B4 (according to panel reactive antibody [PRA] positivity and ABO blood type) and A1 to A4 (based on the maximal PRA% and blood type), respectively. Competing risk and Cox regression analyses were performed to assess the effects of PRA and blood type on graft failure and mortality, respectively. Based on DDKT opportunities and posttransplant outcomes, a new scoring system for kidney allocation was developed. Results: The national and hospital cohorts included 3,311 and 819 patients, respectively, who underwent DDKT. Despite the disparities in DDKT opportunities, the graft failure rates and mortality did not differ among the different PRA and blood type groups. Furthermore, posttransplantation outcomes did not differ according to the categories with different DDKT opportunities. A new scoring system to provide additional points to disadvantaged populations was developed based on the hazard ratios for DDKT. Conclusion: A new allocation approach based on PRA and ABO blood types offers benefits to disadvantaged patients with fewer DDKT opportunities and could enhance equity without sacrificing utility in Korea, which has a long waiting time for DDKT.

Association of Serum Osteoprotegerin With Vascular Calcification, and Cardiovascular and Graft Outcomes in Kidney Transplant Patients: Results From the KNOW-KT.

BACKGROUND: Vascular calcification and stiffness contribute to increased cardiovascular morbidity in patients with chronic kidney disease. This study investigated associations between serum osteoprotegerin (OPG) levels and vascular calcification or stiffness to assess cardiovascular and graft outcomes in kidney transplant patients. METHODS: The KoreaN cohort study for Outcome in patients With Kidney Transplantation was a prospective multicenter cohort study. Serum OPG levels were measured at baseline and 3 y after transplantation in 1018 patients. Patients were classified into high and low OPG groups according to median serum OPG levels. The median follow-up duration was 93.5 mo. RESULTS: The mean age was 45.8 ±â€…11.7 y and 62.9% were men. Patients with high OPG had significantly higher coronary artery calcium scores, abdominal aortic calcification scores, and brachial-ankle pulse wave velocities than those with lower OPG; these parameters remained significant for 5 y after transplantation. The 3-y OPG levels were lower than baseline values ( P < 0.001) and were positively correlated ( r = 0.42, P < 0.001). Multivariate Cox regression analysis showed that high OPG levels were significantly associated with posttransplant cardiovascular events ( P = 0.008) and death-censored graft loss ( P = 0.004). Similar findings regarding posttransplant cardiovascular events ( P = 0.012) and death-censored graft loss ( P = 0.037) were noted in patients with high OPG at the 3-y follow-up. Mediation analyses revealed that coronary artery calcium scores, abdominal aortic calcification scores, and brachial-ankle pulse wave velocities could act as mediators between serum OPG levels and posttransplant cardiovascular events. CONCLUSIONS: Serum OPG concentration is associated with vascular calcification and stiffness and could be a significant risk factor for cardiovascular outcomes and graft loss in patients undergoing kidney transplantation.

Association of Serum Activin Levels with Allograft Outcomes in Patients with Kidney Transplant: Results from the KNOW-KT.

INTRODUCTION: Serum activin A has been reported to contribute to vascular calcification and kidney fibrosis in chronic kidney disease. We aimed to investigate whether higher serum activin levels were associated with poor allograft outcomes in patients with kidney transplantation (KT). METHODS: A total of 860 KT patients from KNOW-KT (Korean Cohort Study for Outcome in Patients with Kidney Transplantation) were analyzed. We measured serum activin levels pre-KT and 1 year after KT. The primary outcome was the composite of a ≥50% decline in estimated glomerular filtration rate and graft failure. Multivariable cause-specific hazard model was used to analyze association of 1-year activin levels with the primary outcome. The secondary outcome was coronary artery calcification score (CACS) at 5 years after KT. RESULTS: During the median follow-up of 6.7 years, the primary outcome occurred in 109 (12.7%) patients. The serum activin levels at 1 year were significantly lower than those at pre-KT (488.2 ± 247.3 vs. 704.0 ± 349.6). When patients were grouped based on the median activin level at 1 year, the high-activin group had a 1.91-fold higher risk (95% CI, 1.25-2.91) for the primary outcome compared to the low-activin group. A one-standard deviation increase in activin levels as a continuous variable was associated with a 1.36-fold higher risk (95% CI, 1.16-1.60) for the primary outcome. Moreover, high activin levels were significantly associated with 1.56-fold higher CACS (95% CI, 1.12-2.18). CONCLUSION: Post-transplant activin levels were independently associated with allograft functions as well as coronary artery calcification in KT patients.

Obstructive Uropathy Caused by Massive Fecal Impaction in a Patient With Congenital Anorectal Malformation and Neurogenic Bladder.

Anorectal malformations (ARMs) comprise a broad spectrum of congenital anomalies involving both anorectal and urogenital tracts. After diagnosis, urological problems should be evaluated in addition to surgical correction of ARMs. Commonly encountered urological problems in patients with ARMs are recurrent urinary tract infections, vesicoureteral reflux, and chronic kidney disease. Therefore, the proper timing of urination and appropriate defecation habits are essential for preserving renal function in patients with ARMs. Here, we report a case of acute hydronephrosis by severe stool impaction in a patient with a history of congenital ARMs and neurogenic bladder. In this case, the physicians should consider properly managing chronic constipation and urination in patients with ARMs despite successful surgical corrections.

High pretransplant FGF23 level is associated with persistent vitamin D insufficiency and poor graft survival in kidney transplant patients.

Vitamin D3 (25[OH]D3) insufficiency and fibroblast growth factor 23 (FGF23) elevation are usually attenuated after kidney transplantation (KT). However, elevated FGF23 may be associated with poor graft outcomes and vitamin D insufficiency after KT. This study investigated the effect of pretransplant FGF23 levels on post-KT 25(OH)D3 status and graft outcomes. Serum FGF23 levels from 400 participants of the KoreaN Cohort Study for Outcome in Patients With Kidney Transplantation were measured. Annual serum 25(OH)D3 levels, all-cause mortality, cardiovascular event, and graft survival were assessed according to baseline FGF23 levels. Serum 25(OH)D3 levels were initially increased 1 year after KT (12.6 ± 7.4 vs. 22.6 ± 6.4 ng/mL). However, the prevalence of post-KT vitamin D deficiency increased again after post-KT 3 years (79.1% at baseline, 30.8% and 37.8% at 3 and 6 years, respectively). Serum FGF23 level was decreased 3 years post-KT. When participants were categorized into tertiles according to baseline FGF23 level (low, middle, high), 25(OH)D3 level in the low FGF23 group was persistently low at a median follow-up of 8.3 years. Furthermore, high baseline FGF23 level was a risk factor for poor graft survival (HR 5.882, 95% C.I.; 1.443-23.976, P = 0.013). Elevated FGF23 levels are associated with persistently low post-transplant vitamin D levels and poor graft survival.

Graft lymphoma in a kidney transplant recipient: a case report.

Posttransplant lymphoproliferative disorders (PTLDs) are severe complications with heterogeneous clinical pictures involving abnormal lymphoproliferation in solid organ transplants and are known to be closely associated with Epstein-Barr virus (EBV) infection. Herein, we present a case of graft lymphoma in a febrile kidney transplant recipient. A 37-year-old woman was admitted with an abrupt 39 °C fever, mild graft discomfort, and gross hematuria. She had received deceased donor kidney transplantation 8 years earlier, but developed graft failure due to a recurrence of immunoglobulin A nephropathy. Laboratory tests revealed anemia and elevated levels of inflammatory markers. Enhanced abdominopelvic computed tomography showed graft swelling with perirenal fat stranding. Thus, we administered antibiotics for a urinary tract infection and increased the doses of steroids due to suspicion of graft intolerance syndrome. However, the patient's symptoms gradually worsened. Eventually, we performed graft nephrectomy and histologically confirmed EBV-positive diffuse large B cell lymphoma. We report a case in which a PTLD was considered in the differential diagnosis of a kidney transplant recipient with symptoms similar to those of a urinary tract infection or graft intolerance syndrome.

Association between sclerostin levels and vascular outcomes in kidney transplantation patients.

BACKGROUND: The impact of circulating sclerostin levels on vascular calcification has shown conflicting results depending on the target population and vascular anatomy. This study investigated the associations of sclerostin levels with vascular outcomes in kidney transplant patients. METHODS: In a prospective observational study of the Korean Cohort Study for Outcome in Patients with Kidney Transplantation, 591 patients with serum sclerostin level data prior to transplantation were analyzed. The main predictor was the pre-transplant sclerostin level. Vascular outcomes were the abdominal aortic calcification score and brachial-ankle pulse wave velocity measured at pre-transplant screening and three and five years after kidney transplantation. RESULTS: In linear regression analysis, sclerostin level positively correlated with changes in abdominal aortic calcification score between baseline and five years after kidney transplantation (coefficient of 0.73 [95% CI, 0.11-1.35] and 0.74 [95% CI, 0.06-1.42] for second and third tertiles, respectively, vs the first tertile). In a longitudinal analysis over five years, using generalized estimating equations, the coefficient of the interaction (sclerostin × time) was significant with a positive value, indicating that higher sclerostin levels were associated with faster increase in post-transplant abdominal aortic calcification score. Linear regression analysis revealed a positive association between pre-transplant sclerostin levels and changes in brachial-ankle pulse wave velocity (coefficient of 126.7 [95% CI, 35.6-217.8], third vs first tertile). Moreover, a significant interaction was identified between sclerostin levels and brachial-ankle pulse wave velocity at five years. CONCLUSIONS: Elevated pre-transplant sclerostin levels are associated with the progression of post-transplant aortic calcifications and arterial stiffness.

Hyperactivation of YAP/TAZ Drives Alterations in Mesangial Cells through Stabilization of N-Myc in Diabetic Nephropathy.

SIGNIFICANCE STATEMENT: Mesangial cells (MCs) in the kidney are essential to maintaining glomerular integrity, and their impairment leads to major glomerular diseases including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying mechanism is poorly understood. We show that YAP/TAZ are increased in MCs of patients with DN and two animal models of DN. High glucose directly induces activation of YAP/TAZ through the canonical Hippo pathway in cultured MCs. Hyperactivation of YAP/TAZ in mouse MCs recapitulates the hallmarks of DN. Activated YAP/TAZ bind and stabilize N-Myc, one of the Myc family. N-Myc stabilization leads to aberrant enhancement of its transcriptional activity and to MC impairments. Our findings shed light on how high blood glucose in diabetes mellitus leads to DN and support a rationale that lowering blood glucose in diabetes mellitus could delay DN pathogenesis. BACKGROUND: Mesangial cells (MCs) in the kidney are central to maintaining glomerular integrity, and their impairment leads to major glomerular diseases, including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying molecular mechanism is poorly understood. METHODS: Immunolocalization of YAP/TAZ and pathological features of PDGFRß + MCs were analyzed in the glomeruli of patients with DN, in Zucker diabetic fatty rats, and in Lats1/2i ΔPß mice. RiboTag bulk-RNA sequencing and transcriptomic analysis of gene expression profiles of the isolated MCs from control and Lats1/2iΔPß mice were performed. Immunoprecipitation analysis and protein stability of N-Myc were performed by the standard protocols. RESULTS: YAP and TAZ, the final effectors of the Hippo pathway, are highly increased in MCs of patients with DN and in Zucker diabetic fatty rats. Moreover, high glucose directly induces activation of YAP/TAZ through the canonical Hippo pathway in cultured MCs. Hyperactivation of YAP/TAZ in mouse model MCs recapitulates the hallmarks of DN, including excessive proliferation of MCs and extracellular matrix deposition, endothelial cell impairment, glomerular sclerosis, albuminuria, and reduced glomerular filtration rate. Mechanistically, activated YAP/TAZ bind and stabilize N-Myc protein, one of the Myc family of oncogenes. N-Myc stabilization leads to aberrant enhancement of its transcriptional activity and eventually to MC impairments and DN pathogenesis. CONCLUSIONS: Our findings shed light on how high blood glucose in diabetes mellitus leads to DN and support a rationale that lowering blood glucose in diabetes mellitus could delay DN pathogenesis.

Impact of iron status on kidney outcomes in kidney transplant recipients.

Iron plays an important role in hemodynamics and the immunity, independent of anemia. Since dynamic changes occur in iron storage after kidney transplantation (KT), we investigated the association between iron status and kidney outcomes in KT patients. We analyzed data from the KoreaN cohort study for Outcome in patients With KT (KNOW-KT). The iron status was classified into three groups based on ferritin or transferrin saturation (TSAT) levels one year after KT, with reference ranges of 20‒35% and 100‒300 ng/mL for TSAT and ferritin, respectively. The primary outcome was the composite outcome, which consisted of death, graft failure, and an estimated glomerular filtration rate decline ≥ 50%. In total, 895 patients were included in the final analysis. During a median follow-up of 5.8 years, the primary outcome occurred in 94 patients (19.8/1000 person-years). TSAT levels decreased one year after KT and thereafter gradually increased, whereas ferritin levels were maintained at decreased levels. The adjusted hazard ratios (95% confidence intervals) for the composite outcome were 1.67 (1.00-2.77) and 1.20 (0.60-2.40) in the TSAT > 35% and ferritin > 300 ng/mL groups, respectively. High iron status with high TSAT levels increases the risk of graft failure or kidney functional deterioration after KT.

Loss of Proximal Tubular Sirtuin 6 Aggravates Unilateral Ureteral Obstruction-Induced Tubulointerstitial Inflammation and Fibrosis by Regulation of ß-Catenin Acetylation.

Renal fibrosis is a significant pathologic change associated with progressive kidney disease. Sirt6 is an NAD+-dependent deacetylase and mono-ADP ribosyltransferase known to play diverse roles in the processes attendant to aging, metabolism, and carcinogenesis. However, the role of proximal tubule-specific Sirt6 in renal fibrosis remains elusive. This study investigates the effect of proximal tubule-specific Sirt6 knockdown on unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial inflammation and fibrosis. Renal fibrosis in wild type and PT-Sirt6KO (Sirt6flox/flox; Ggt1-Cre+) mice was induced by UUO surgery. After seven days, histologic examination and Western blot analysis were performed to examine extracellular matrix (ECM) protein expression. We evaluated inflammatory cytokine and cell adhesion molecule expression after ureteral obstruction. The therapeutic effect of Sirt6 activator MDL-800 on UUO-induced tubulointerstitial inflammation and fibrosis was assessed. The loss of Sirt6 in the proximal tubules aggravated UUO-induced tubular injury, ECM deposition, F4/80 positive macrophage infiltration, and proinflammatory cytokine and chemokine expression. Sirt6 activator MDL-800 mitigated UUO-induced renal tubulointerstitial inflammation and fibrosis. In an in vitro experiment, MDL-800 decreases the transforming growth factor (TGF)-ß1-induced activation of myofibroblast and ECM production by regulating Sirt6-dependent ß-catenin acetylation and the TGF-ß1/Smad signaling pathway. In conclusion, proximal tubule Sirt6 may play an essential role in UUO-induced tubulointerstitial inflammation and fibrosis by regulating Sirt6-dependent ß-catenin acetylation and ECM protein promoter transcription.

Copy number variation analysis using next-generation sequencing identifies the CFHR3/CFHR1 deletion in atypical hemolytic uremic syndrome: a case report.

OBJECTIVES: Atypical hemolytic uremic syndrome (aHUS) is characterized by a triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure resulting from platelet thrombi in the microcirculation of the kidney and other organs, in the absence of a preceding diarrheal illness. This report describes a case in which copy number variation (CNV) analysis using next-generation sequencing (NGS) identified the CFHR3/CFHR1 deletion in a patient with aHUS. METHODS: A 49-year-old Korean female was diagnosed with aHUS based on clinical findings, including schistocytes in peripheral blood and marked thrombocytopenia, suggesting the presence of thrombotic microangiopathy, elevated serum lactate dehydrogenase, and acute kidney injury. Sequence variants and CNV generated from NGS data were estimated to determine if there was a potential genetic cause. Multiplex ligation-dependent probe amplification (MLPA) was conducted to confirm the CFHR3/CFHR1 deletion identified by NGS with CNV analysis. RESULTS: No known or novel pathogenic single nucleotide variant or small insertion/deletion that would be predicted to have damaging effects that could lead to aHUS were identified. However, CNV analysis of NGS data identified the heterozygous CFHR3/CFHR1 deletion. MLPA confirmed this loss of one copy number between the CFHR3 and the CFHR1 genes on chromosome 1q31.3. CONCLUSION: We genetically diagnosed a Korean woman harboring a heterozygous CFHR3/CFHR1 deletion of a known causative gene for aHUS. Our report emphasizes the need for CNV analysis of NGS data and gene dosage assays, such as MLPA, to evaluate large-scale deletions or duplications and generate hybrid CFH genes in patients with suspected aHUS.

Collapsing focal segmental glomerulosclerosis in a patient with oral cavity cancer: A case report.

RATIONALE: Focal segmental glomerulosclerosis (FSGS) is one of the most common glomerular diseases, leading to end-stage renal disease. Among the 5 variants of FSGS, the collapsing variant is rare and has the worst prognosis. Solid and hematologic malignancies are associated with glomerular diseases, such as membranous nephropathy, minimal change disease, and FSGS. However, squamous cell carcinoma of the oral cavity is rarely associated with nephrotic syndrome, especially FSGS. PATIENT CONCERNS: A 55-year-old woman diagnosed with oral cavity cancer presented with generalized edema with heavy proteinuria and renal dysfunction after neoadjuvant chemotherapy and wide surgical excision. DIAGNOSIS: Renal biopsy shows segmental or global collapse of glomerular capillaries with marked hyperplasia and swelling of overlying epithelial cells, suggesting a collapsing variant of FSGS. INTERVENTIONS: After the renal biopsy, we prescribed oral prednisolone at a dose of 1 mg/kg/day. Despite immunosuppressive treatment, renal function deteriorated, and hemodialysis was started. OUTCOMES: After 23 sessions of hemodialysis and high-dose oral glucocorticoid treatment, renal function gradually improved, and oral glucocorticoid therapy was discontinued after 8 months. Currently, this patient is in a cancer-free state and has normal renal function without proteinuria. LESSONS: Unusual collapsing FSGS might be associated with neoadjuvant chemotherapy and wide surgical excision in patients with oral cavity cancer. Proper diagnostic workup, such as renal biopsy and high-dose glucocorticoid therapy, might have helped recover from nephrotic syndrome and acute renal injury in cancer patients.

The Association between Serum Hemoglobin and Renal Prognosis of IgA Nephropathy.

Immunoglobin A (IgA) nephropathy causes chronic kidney disease worldwide. Therefore, identifying risk factors associated with the progression of IgA nephropathy is crucial. Anemia is a common complication of chronic kidney disease; however, few studies have investigated the effect of serum hemoglobin on the renal prognosis of IgA nephropathy. This study aimed to determine the effect of serum hemoglobin on the progression of IgA nephropathy. We retrospectively analyzed 4326 patients with biopsy-proven IgA nephropathy. We evaluated the effect of serum hemoglobin on IgA nephropathy progression using Kaplan-Meier survival analyses, the log-rank test, and the Cox proportional hazards model. The primary end-point was progression of IgA nephropathy, defined as dialysis initiation or kidney transplantation. Serum hemoglobin showed a nonlinear relationship with the progression of IgA nephropathy. The Cox proportional hazards model showed that the risk of progression of IgA nephropathy decreased 0.87 times for every 1.0 g/dL increase in serum hemoglobin. In subgroup analyses, reduced serum hemoglobin was an independent risk factor for IgA nephropathy progression only in women. There was no statistically significant interaction of serum hemoglobin between men and women (P interaction = 0.177). Results of Sensitivity analysis were robust and consistent. Serum hemoglobin at diagnosis was an independent predictor for IgA nephropathy progression.

Severe anorexia and weight loss induced by tacrolimus in kidney transplant recipients.

Common neuropsychiatric complications of tacrolimus include tremors, fatigue, headache, sleep disorders, paranoid reactions, and anxiety. Other, more serious complications include encephalopathy, convulsions, confusion, and coma. To our knowledge, however, severe weight loss by anorexia has not been reported as a neuropsychiatric adverse effect of tacrolimus given to adult kidney transplant recipients. In this article we present two cases of severe anorexia and weight loss associated with tacrolimus that appeared to reverse with cyclosporine.

Inhibition of Yes-Associated Protein by Verteporfin Ameliorates Unilateral Ureteral Obstruction-Induced Renal Tubulointerstitial Inflammation and Fibrosis.

Yes-associated protein (YAP) activation after acute ischemic kidney injury might be related to interstitial fibrosis and impaired renal tubular regeneration. Verteporfin (VP) is a photosensitizer used in photodynamic therapy to treat age-related macular degeneration. In cancer cells, VP inhibits TEA domain family member (TEAD)-YAP interactions without light stimulation. The protective role of VP in unilateral ureteral obstruction (UUO)-induced renal fibrosis and related mechanisms remains unclear. In this study, we investigate the protective effects of VP on UUO-induced renal tubulointerstitial inflammation and fibrosis and its regulation of the transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway. We find that VP decreased the UUO-induced increase in tubular injury, inflammation, and extracellular matrix deposition in mice. VP also decreased myofibroblast activation and proliferation in UUO kidneys and NRK-49F cells by modulating Smad2 and Smad3 phosphorylation. Therefore, YAP inhibition might have beneficial effects on UUO-induced tubulointerstitial inflammation and fibrosis by regulating the TGF-ß1/Smad signaling pathway.

SIRT2 is involved in cisplatin-induced acute kidney injury through regulation of mitogen-activated protein kinase phosphatase-1.

BACKGROUND: Activation of mitogen-activated protein kinase phosphatase-1 (MKP-1), a dual-specificity protein phosphatase, regulates mitogen-activated protein kinase signaling. C-Jun N-terminal kinase (JNK) and p38 are activated in cisplatin-induced renal injury. However, the change of MKP-1 expression in cisplatin-induced renal injury and the regulatory effect of sirtuin 2 (SIRT2), a nicotinamide adenine dinucleotide-dependent deacetylase, on MKP-1 remains unknown. METHODS: To address these issues, we used constitutional Sirt2 knockout (KO) mice, transgenic (TG) mice with increased expression of SIRT2 specifically in proximal tubular epithelial cellsand wild-type (WT) mice. Cisplatin nephrotoxicity was induced by intraperitoneal injection of cisplatin. RESULTS: MKP-1 expression in the kidney was decreased after cisplatin treatment. Cisplatin-induced downregulation of MKP-1 was reversed in Sirt2 KO mice kidney and further decreased in Sirt2 TG mice kidney. We observed similar phenomenon with SIRT2-knockdown or SIRT2-overexpressed tubular epithelial cells. Phosphorylation of p38 and JNK, a downstream signal pathway of MKP-1, increased in WT mice kidney following treatment with cisplatin. A decrease in SIRT2 suppressed cisplatin-induced phosphorylation of p38 and JNK in kidney and tubular epithelial cells. Overexpression of SIRT2 further increased phosphorylation of p38 and JNK in kidney and tubular epithelial cells. Acetylation of MKP-1 was significantly increased in SIRT2-knockdown cells and decreased in SIRT2-overexpressed cells after cisplatin stimulation. Sirt2 KO mice and Sirt2 TG mice showed amelioration and aggravation of renal injury, apoptosis, necroptosis and inflammation induced by cisplatin. CONCLUSION: Our data show that SIRT2 is associated with cisplatin-induced renal injury through regulation of MKP-1 expression.

SIRT1 induces the adipogenic differentiation of mouse embryonic stem cells by regulating RA-induced RAR expression via NCOR1 acetylation.

SIRT1 (NAD+-dependent deacetylase) plays a suppressive role during the late stages of adipogenesis. However, the effects of SIRT1 on the early phases of adipogenic differentiation from embryonic stem cells (ESCs) are poorly understood. We employed Sirt1+/+ and Sirt1-/- mouse embryonic stem cells (mESCs) to evaluate the role of SIRT1 during the early stage mESC differentiation to adipocytes in response to retinoic acid (RA) treatment. Treatment with EX527 (a SIRT1 inhibitor) during the early phase and SIRT1 knockout both significantly diminished differentiation to mature adipocytes. Expressions of marker genes of preadipocytes, brown adipocytes, and brite cells were significantly lower in Sirt1-/- mESCs than in Sirt1+/+ mESCs. Furthermore, SIRT1 knockout reduced RA-induced RA receptor (RAR)α and RARß mRNA and protein expressions during early adipocyte differentiation. Nuclear receptor corepressor 1 (NCOR1), a negative regulator of RAR signaling, expression, and acetylation levels were higher in Sirt1-/- than in Sirt1+/+ mESCs. After RA treatment, chromatin immunoprecipitation assays using an antibody against NCOR1, revealed that NCOR1 binding to RARß promoters was significantly lower in Sirt1-/- mESCs than in Sirt1+/+ mESCs, and luciferase reporter assays showed SIRT1 knockdown decreased RA-induced RARα activity. Taken together, these observations show SIRT1 is required during the early phase of mESC adipogenesis and that SIRT1 deficiency inhibits adipogenesis by increasing NCOR1 acetylation and down-regulating the expressions of RARα and RARß.

Sirtuin 3 Activation by Honokiol Decreases Unilateral Ureteral Obstruction-Induced Renal Inflammation and Fibrosis via Regulation of Mitochondrial Dynamics and the Renal NF-κBTGF-ß1/Smad Signaling Pathway.

Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirtuin 3(SIRT3) is one of the mitochondrial sirtuins, and plays a role in the regulation of mitochondrialbiogenesis, oxidative stress, fatty acid metabolism, and aging. Recently, honokiol (HKL), as apharmaceutical SIRT3 activator, has been observed to have a protective effect against pressureoverload-induced cardiac hypertrophy by increasing SIRT3 activity. In this study, we investigatedwhether HKL, as a SIRT3 activator, also has protective effects against unilateral ureteral obstruction(UUO)-induced renal tubulointerstitial fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the nuclear factor-κB (NF-κB)/transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway. We found that HKL decreased the UUO-induced increase in tubularinjury and extracellular matrix (ECM) deposition in mice. HKL also decreased myofibroblastactivation and proliferation in UUO kidneys and NRK-49F cells. Finally, we showed that HKLtreatment decreased UUO-induced mitochondrial fission and promoted mitochondrial fusionthrough SIRT3-dependent effects. In conclusion, activation of SIRT3 via HKL treatment might havebeneficial effects on UUO-induced renal fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the NF-κB/TGF-ß1/Smad signaling pathway.