Renal pathology in a mouse model of severe Spinal Muscular Atrophy is associated with downregulation of Glial Cell-Line Derived Neurotrophic Factor (GDNF).
Hum Mol Genet
; 29(14): 2365-2378, 2020 08 11.
Article
em En
| MEDLINE
| ID: mdl-32588893
Spinal muscular atrophy (SMA) occurs as a result of cell-ubiquitous depletion of the essential survival motor neuron (SMN) protein. Characteristic disease pathology is driven by a particular vulnerability of the ventral motor neurons of the spinal cord to decreased SMN. Perhaps not surprisingly, many other organ systems are also impacted by SMN depletion. The normal kidney expresses very high levels of SMN protein, equivalent to those found in the nervous system and liver, and levels are dramatically lowered by ~90-95% in mouse models of SMA. Taken together, these data suggest that renal pathology may be present in SMA. We have addressed this using an established mouse model of severe SMA. Nephron number, as assessed by gold standard stereological techniques, was significantly reduced. In addition, morphological assessment showed decreased renal vasculature, particularly of the glomerular capillary knot, dysregulation of nephrin and collagen IV, and ultrastructural changes in the trilaminar filtration layers of the nephron. To explore the molecular drivers underpinning this process, we correlated these findings with quantitative PCR measurements and protein analyses of glial cell-line-derived neurotrophic factor, a crucial factor in ureteric bud branching and subsequent nephron development. Glial cell-line-derived neurotrophic factor levels were significantly reduced at early stages of disease in SMA mice. Collectively, these findings reveal significant renal pathology in a mouse model of severe SMA, further reinforcing the need to develop and administer systemic therapies for this neuromuscular disease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Atrofia Muscular Espinal
/
Fator Neurotrófico Derivado de Linhagem de Célula Glial
/
Neurônios Motores
/
Doenças Neuromusculares
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article