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1.
Mar Drugs ; 19(4)2021 Mar 26.
Article in English | MEDLINE | ID: mdl-33810216

ABSTRACT

Mitochondrial dysfunction contributes to the pathogenesis of kidney injury related with cardiovascular disease. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) protects renal tubular cells by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2). AMP-activated protein kinase (pAMPK)-mediated phosphorylation and sirtuin 1/3 (SIRT1/3)-mediated deacetylation are required for PGC-1α activation. In the present study, we aimed to investigate whether omega-3 fatty acids (FAs) regulate the expression of mediators of mitochondrial biogenesis in 5/6 nephrectomy (Nx) rats. Male Sprague-Dawley rats were assigned to the following groups: sham control, Nx, and Nx treated with omega-3 FA. The expression of PGC-1α, phosphorylated PGC-1α (pPGC-1α), acetylated PGC-1α, and factors related to mitochondrial biogenesis was examined through Western blot analysis. Compared to the control group, the expression of PGC-1α, pAMPK, SIRT1/3, Nrf1, mTOR, and Nrf2 was significantly downregulated, and that of Keap 1, acetylated PGC-1α, and FoxO1/3, was significantly upregulated in the Nx group. These changes in protein expression were rescued in the omega-3 FA group. However, the expression of pPGC-1α was similar among the three groups. Omega-3 FAs may involve mitochondrial biogenesis by upregulating Nrf1 and Nrf2. This protective mechanism might be attributed to the increased expression and deacetylation of PGC-1α, which was triggered by SIRT1/3.


Subject(s)
Fatty Acids, Omega-3/pharmacology , Kidney Diseases/drug therapy , Kidney/drug effects , Mitochondria/drug effects , Nuclear Respiratory Factor 1/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Sirtuin 1/metabolism , Sirtuins/metabolism , Acetylation , Animals , Disease Models, Animal , Kidney/enzymology , Kidney/pathology , Kidney Diseases/enzymology , Kidney Diseases/etiology , Kidney Diseases/pathology , Male , Mitochondria/enzymology , Mitochondria/pathology , NF-E2-Related Factor 2/metabolism , Nephrectomy , Organelle Biogenesis , Protein Processing, Post-Translational , Rats, Sprague-Dawley , Signal Transduction
2.
BioDrugs ; 34(1): 99-110, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31749113

ABSTRACT

BACKGROUND: Darbepoetin-alfa is an erythropoiesis-stimulating agent (ESA) with a long elimination half-life that achieves better hemoglobin (Hb) stability than short-acting ESAs. OBJECTIVE: We aimed to evaluate the efficacy and safety of intravenous CKD-11101 (a biosimilar of darbepoetin-alfa) compared with those of darbepoetin-alfa in hemodialysis patients. METHODS: The study was performed in 24 centers in Korea between June 2015 and June 2017. The study subjects were randomized in a double-blind manner. The follow-up duration was 24 weeks, which consisted of 20 weeks of maintenance and 4 weeks of evaluation period. All patients underwent a stabilization period to achieve a target baseline Hb of 10-12 g/dL before randomization. Following randomization, patients received darbepoetin-alfa or CKD-11101 weekly or biweekly. RESULTS: A total of 403 patients were randomized into two groups, and a total of 325 patients (80.6%) completed the investigation. The differences between the two groups in terms of change in the average Hb level from baseline to evaluation were not significant. The average administered dose of ESA was similar between the groups. There was no difference in the proportion of patients who maintained the target Hb during the evaluation period [60.4% vs. 66.2% in the CKD-11101 and darbepoetin-alfa groups, respectively (p = 0.3038)]. In addition, the safety analysis, consisting of adverse events and adverse drug reactions, showed comparable results between the two groups. CONCLUSION: The changes in the level of Hb, dose of erythropoietin, and achievement rate of the target Hb during the study period were comparable between the groups. CKD-11101 has an equivalent efficacy and safety compared with darbepoetin-alfa in patients undergoing hemodialysis.


Subject(s)
Biosimilar Pharmaceuticals/adverse effects , Biosimilar Pharmaceuticals/therapeutic use , Darbepoetin alfa/adverse effects , Darbepoetin alfa/therapeutic use , Epoetin Alfa/adverse effects , Epoetin Alfa/pharmacology , Renal Insufficiency, Chronic/drug therapy , Adult , Double-Blind Method , Drug-Related Side Effects and Adverse Reactions/etiology , Female , Hemoglobins/metabolism , Humans , Male , Middle Aged , Renal Dialysis/methods , Renal Insufficiency, Chronic/metabolism
3.
J Clin Invest ; 124(3): 1098-113, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24531545

ABSTRACT

Podocytes are specialized actin-rich epithelial cells that line the kidney glomerular filtration barrier. The interface between the podocyte and the glomerular basement membrane requires integrins, and defects in either α3 or ß1 integrin, or the α3ß1 ligand laminin result in nephrotic syndrome in murine models. The large cytoskeletal protein talin1 is not only pivotal for integrin activation, but also directly links integrins to the actin cytoskeleton. Here, we found that mice lacking talin1 specifically in podocytes display severe proteinuria, foot process effacement, and kidney failure. Loss of talin1 in podocytes caused only a modest reduction in ß1 integrin activation, podocyte cell adhesion, and cell spreading; however, the actin cytoskeleton of podocytes was profoundly altered by the loss of talin1. Evaluation of murine models of glomerular injury and patients with nephrotic syndrome revealed that calpain-induced talin1 cleavage in podocytes might promote pathogenesis of nephrotic syndrome. Furthermore, pharmacologic inhibition of calpain activity following glomerular injury substantially reduced talin1 cleavage, albuminuria, and foot process effacement. Collectively, these findings indicate that podocyte talin1 is critical for maintaining the integrity of the glomerular filtration barrier and provide insight into the pathogenesis of nephrotic syndrome.


Subject(s)
Glomerular Filtration Barrier/pathology , Nephrotic Syndrome/metabolism , Podocytes/metabolism , Talin/physiology , Actin Cytoskeleton/metabolism , Animals , Calpain/metabolism , Cell Adhesion , Cells, Cultured , Focal Adhesions/metabolism , Humans , Integrin beta1/metabolism , Mice , Mice, Knockout , Nephrotic Syndrome/pathology , Proteinuria/genetics , Proteinuria/metabolism , Proteolysis , Renal Insufficiency/genetics , Renal Insufficiency/metabolism
4.
J Clin Invest ; 122(12): 4401-11, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23187129

ABSTRACT

Podocytes are specialized cells that play an integral role in the renal glomerular filtration barrier via their foot processes. The foot processes form a highly organized structure, the disruption of which causes nephrotic syndrome. Interestingly, several similarities have been observed between mechanisms that govern podocyte organization and mechanisms that mediate neuronal synapse development. Dynamin, synaptojanin, and endophilin are functional partners in synaptic vesicle recycling via interconnected actions in clathrin-mediated endocytosis and actin dynamics in neurons. A role of dynamin in the maintenance of the kidney filtration barrier via an action on the actin cytoskeleton of podocytes was suggested. Here we used a conditional double-KO of dynamin 1 (Dnm1) and Dnm2 in mouse podocytes to confirm dynamin's role in podocyte foot process maintenance. In addition, we demonstrated that while synaptojanin 1 (Synj1) KO mice and endophilin 1 (Sh3gl2), endophilin 2 (Sh3gl1), and endophilin 3 (Sh3gl3) triple-KO mice had grossly normal embryonic development, these mutants failed to establish a normal filtration barrier and exhibited severe proteinuria due to abnormal podocyte foot process formation. These results strongly implicate a protein network that functions at the interface between endocytosis and actin at neuronal synapses in the formation and maintenance of the kidney glomerular filtration barrier.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Dynamin II/genetics , Dynamin I/genetics , Glomerular Filtration Barrier/pathology , Nerve Tissue Proteins/genetics , Phosphoric Monoester Hydrolases/genetics , Podocytes/metabolism , Actins/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cells, Cultured , Dynamin I/metabolism , Dynamin II/metabolism , Endocytosis , Glomerular Filtration Barrier/metabolism , Mice , Mice, Knockout , Microscopy, Confocal , Microscopy, Fluorescence , Nerve Tissue Proteins/metabolism , Phosphoric Monoester Hydrolases/metabolism , Proteinuria/genetics , Proteinuria/pathology , Renal Insufficiency/genetics , Renal Insufficiency/pathology , Renal Insufficiency/urine
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