PloS one, 2020, Vol.15 (3), p.e0229397-e0229397
2020
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- Autor(en) / Beteiligte
- Titel
- Podocyte-specific deletion of tubular sclerosis complex 2 promotes focal segmental glomerulosclerosis and progressive renal failure
- Ist Teil von
- PloS one, 2020, Vol.15 (3), p.e0229397-e0229397
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Obesity can initiate and accelerate the progression of kidney diseases. However, it remains unclear how obesity affects renal dysfunction. Here, we show that a newly generated podocyte-specific tubular sclerosis complex 2 (Tsc2) knockout mouse model (Tsc2Δpodocyte) develops proteinuria and dies due to end-stage renal dysfunction by 10 weeks of age. Tsc2Δpodocyte mice exhibit an increased glomerular size and focal segmental glomerulosclerosis, including podocyte foot process effacement, mesangial sclerosis and proteinaceous casts. Podocytes isolated from Tsc2Δpodocyte mice show nuclear factor, erythroid derived 2, like 2-mediated increased oxidative stress response on microarray analysis and their autophagic activity is lowered through the mammalian target of rapamycin (mTOR)-unc-51-like kinase 1 pathway. Rapamycin attenuated podocyte dysfunction and extends survival in Tsc2Δpodocyte mice. Additionally, mTOR complex 1 (mTORC1) activity is increased in podocytes of renal biopsy specimens obtained from obese patients with chronic kidney disease. Our work shows that mTORC1 hyperactivation in podocytes leads to severe renal dysfunction and that inhibition of mTORC1 activity in podocytes could be a key therapeutic target for obesity-related kidney diseases.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0229397Titel-ID: cdi_plos_journals_2379557898
- Format
- –
- Schlagworte
- Age, Animals, Autophagy, Biology and Life Sciences, Biopsy, Cancer, Cardiovascular disease, Childrens health, Cytokines, Diabetes, Disease Models, Animal, Disease Progression, End-stage renal disease, Endocrinology, Genotype & phenotype, Glomerulosclerosis, Focal Segmental - etiology, Glomerulosclerosis, Focal Segmental - metabolism, Glomerulosclerosis, Focal Segmental - pathology, Humans, Immunology, Kidney diseases, Kidneys, Kinases, Laboratories, Male, Mechanistic Target of Rapamycin Complex 1 - metabolism, Medical research, Medicine, Medicine and Health Sciences, Metabolism, Mice, Mice, Knockout, Mice, Obese, Nephrology, Obesity, Obesity - complications, Oxidative stress, Podocytes - metabolism, Podocytes - pathology, Proteinuria, Rapamycin, Renal failure, Renal function, Renal Insufficiency, Chronic - etiology, Renal Insufficiency, Chronic - metabolism, Renal Insufficiency, Chronic - pathology, Research and Analysis Methods, Sclerosis, Survival analysis, Therapeutic applications, TOR protein, Tuberous Sclerosis Complex 2 Protein - physiology