Prevention of apoptosis averts glomerular tubular disconnection and podocyte loss in proteinuric kidney disease
2016 (English)In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 90, no 1, 135-148 p.Article in journal (Refereed) PublishedText
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.
Place, publisher, year, edition, pages
Nature Publishing Group, 2016. Vol. 90, no 1, 135-148 p.
albuminuria, apoptosis, cell signaling, chronic kidney disease, ouabain, podocyte, proximal tubule, sodium potassium adenosine tri-phosphatase, a-tubular glomeruli
Urology and Nephrology
IdentifiersURN: urn:nbn:se:kth:diva-189657DOI: 10.1016/j.kint.2016.03.026ISI: 000377929400022PubMedID: 27217195OAI: oai:DiVA.org:kth-189657DiVA: diva2:949032
FunderSwedish Research CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
QC 201607152016-07-152016-07-112016-07-15Bibliographically approved