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mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans.
- Source :
-
JCI insight [JCI Insight] 2019 Sep 19; Vol. 4 (18). Date of Electronic Publication: 2019 Sep 19. - Publication Year :
- 2019
-
Abstract
- The cellular origins of glomerulosclerosis involve activation of parietal epithelial cells (PECs) and progressive podocyte depletion. While mammalian target of rapamycin-mediated (mTOR-mediated) podocyte hypertrophy is recognized as an important signaling pathway in the context of glomerular disease, the role of podocyte hypertrophy as a compensatory mechanism preventing PEC activation and glomerulosclerosis remains poorly understood. In this study, we show that glomerular mTOR and PEC activation-related genes were both upregulated and intercorrelated in biopsies from patients with focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, suggesting both compensatory and pathological roles. Advanced morphometric analyses in murine and human tissues identified podocyte hypertrophy as a compensatory mechanism aiming to regulate glomerular functional integrity in response to somatic growth, podocyte depletion, and even glomerulosclerosis - all of this in the absence of detectable podocyte regeneration. In mice, pharmacological inhibition of mTOR signaling during acute podocyte loss impaired hypertrophy of remaining podocytes, resulting in unexpected albuminuria, PEC activation, and glomerulosclerosis. Exacerbated and persistent podocyte hypertrophy enabled a vicious cycle of podocyte loss and PEC activation, suggesting a limit to its beneficial effects. In summary, our data highlight a critical protective role of mTOR-mediated podocyte hypertrophy following podocyte loss in order to preserve glomerular integrity, preventing PEC activation and glomerulosclerosis.
- Subjects :
- Aged
Aged, 80 and over
Animals
Biopsy
Cells, Cultured
Child, Preschool
Datasets as Topic
Diabetes Mellitus, Experimental chemically induced
Diabetes Mellitus, Experimental complications
Diabetes Mellitus, Experimental pathology
Diabetic Nephropathies drug therapy
Epithelial Cells pathology
Everolimus administration & dosage
Female
Gene Expression Profiling
Humans
Hypertrophy drug therapy
Hypertrophy pathology
Infant
Male
Mice
Mice, Knockout
Middle Aged
Podocytes
Primary Cell Culture
Regeneration
Signal Transduction drug effects
Signal Transduction genetics
Streptozocin toxicity
TOR Serine-Threonine Kinases analysis
TOR Serine-Threonine Kinases antagonists & inhibitors
Tuberous Sclerosis Complex 1 Protein genetics
Tuberous Sclerosis Complex 1 Protein metabolism
Up-Regulation
Young Adult
Albuminuria chemically induced
Diabetic Nephropathies pathology
Everolimus adverse effects
Glomerulosclerosis, Focal Segmental pathology
TOR Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 4
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 31534053
- Full Text :
- https://doi.org/10.1172/jci.insight.99271