title: Prevention of apoptosis averts glomerular tubular disconnection and podocyte loss in proteinuric kidney disease.
abstract: There is a great need for treatment that arrests progression of chronic kidney disease. Increased albumin in urine leads to apoptosis and fibrosis of podocytes and tubular cells and is a major cause of functional deterioration. There have been many attempts to target fibrosis, but because of the lack of appropriate agents, few have targeted apoptosis. Our group has described an ouabain-activated Na,K-ATPase/IP3R signalosome, which protects from apoptosis. Here we show that albumin uptake in primary rat renal epithelial cells is accompanied by a time- and dose-dependent mitochondrial accumulation of the apoptotic factor Bax, down-regulation of the antiapoptotic factor Bcl-xL and mitochondrial membrane depolarization. Ouabain opposes these effects and protects from apoptosis in albumin-exposed proximal tubule cells and podocytes. The efficacy of ouabain as an antiapoptotic and kidney-protective therapeutic tool was then tested in rats with passive Heymann nephritis, a model of proteinuric chronic kidney disease. Chronic ouabain treatment preserved renal function, protected from renal cortical apoptosis, up-regulated Bax, down-regulated Bcl-xL, and rescued from glomerular tubular disconnection and podocyte loss. Thus we have identified a novel clinically feasible therapeutic tool, which has the potential to protect from apoptosis and rescue from loss of functional tissue in chronic proteinuric kidney disease.
authors.affiliation: Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden.
authors.forename: Ievgeniia
authors.initials: I
authors.lastname: Burlaka
authors.affiliation: Science for Life Laboratory, Department of Applied Physics, Royal Institute of Technology, Solna, Sweden.
authors.forename: Linnéa M
authors.initials: LM
authors.lastname: Nilsson
authors.affiliation: Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden. Electronic address: Lena.Scott@ki.se.
authors.forename: Lena
authors.initials: L
authors.lastname: Scott
authors.affiliation: Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden.
authors.forename: Ulla
authors.initials: U
authors.lastname: Holtbäck
authors.affiliation: Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden.
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Eklöf
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.affiliation: Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden; Science for Life Laboratory, Department of Applied Physics, Royal Institute of Technology, Solna, Sweden.
authors.forename: Hjalmar
authors.initials: H
authors.lastname: Brismar
authors.affiliation: Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden. Electronic address: Anita.Aperia@ki.se.
authors.forename: Anita
authors.initials: A
authors.lastname: Aperia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D015433:Glomerulonephritis, Membranous / Q000188:drug therapy*; D006801:Humans; D007674:Kidney Diseases / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects*; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D008297:Male; D010042:Ouabain / Q000627:therapeutic use*; D050199:Podocytes / Q000502:physiology; D061251:Primary Cell Culture; D011507:Proteinuria / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; C494811:BCL2L1 protein, human; D002316:Cardiotonic Agents; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase
keywords: a-tubular glomeruli; albuminuria; apoptosis; cell signaling; chronic kidney disease; ouabain; podocyte; proximal tubule; sodium potassium adenosine triphosphatase