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Amelioration of Podocytopathy by Smpd1 Gene Deletion in Podocyte‐Specific Asah1 Gene Knockout Mice
Author(s) -
Li Guangbi,
Huang Dandan,
Camus Sarah,
Li Ningjun,
Li Pin-Lan
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06120
Subject(s) - knockout mouse , podocyte , gene knockout , podocin , ceramide , microbiology and biotechnology , biology , endocrinology , gene , kidney , genetics , proteinuria , apoptosis
Podocyte‐specific deletion of Asah1 (AC gene code in mouse) gene has been found to produce podocytopathy and nephrotic syndrome in mice (Asah1 fl/fl /Podo Cre mice). However, the mechanism underlying the pathogenesis of podocytopathy in these mice remains unknown. To test whether ceramide accumulation contributes to podocyte injury in Asah1 fl/fl /Podo Cre mice, Asah1 fl/fl /Podo Cre mice were mated with Smpd1 −/− mice (Smpd1 is mouse gene coding acid sphingomyelinase), which produced mice lacking both Smpd1 and Asah1 gene in podocytes, namely, Smpd1 −/− /Asah1 fl/fl /Podo Cre mice. Using LC‐MS/MS, ceramide accumulation was detected in isolated glomeruli of Asah1 fl/fl /Podo Cre mice, and Smpd1 gene knockout blocked glomerular ceramide accumulation Asah1 fl/fl /Podo Cre mice. Correspondingly, severe proteinuria and albuminuria in Asah1 fl/fl /Podo Cre mice were ameliorated by Smpd1 gene deletion. By immunofluorescence staining, we found reduced glomerular podocin and increased glomerular desmin in Asah1 fl/fl /Podo Cre mice, which was confirmed using Western blot analysis in isolated glomeruli from these mice. All these podocyte injuries in Asah1 fl/fl /Podo Cre mice were substantially blocked by cross breeding with Smpd1 gene knockout mice. Under transmission electron microscope, Asah1 fl/fl /Podo Cre mice were found to have foot process effacement and microvillus formation in podocytes, which were also reversed by deletion of Smpd1 gene. These results suggest that AC deficiency induces ceramide accumulation in mouse glomeruli which is critical to the development of podocytopathy and nephrotic syndrome. Blockade of ceramide production via ASM may attenuate ceramide accumulation and consequent podocytopathy due to AC gene deficiency. Support or Funding Information This study was supported by NIH grants DK54927 and DK102539.