Journal article
Mice with mutant Inf2 show impaired podocyte and slit diaphragm integrity in response to protamine-induced kidney injury
Kidney international, Vol.90(2), pp.363-372
08/01/2016
DOI: 10.1016/j.kint.2016.04.020
PMCID: PMC5363079
PMID: 27350175
Abstract
Mutations in the INF2 (inverted formin 2) gene, encoding a diaphanous formin family protein that regulates actin cytoskeleton dynamics, cause human focal segmental glomerulosclerosis (FSGS). INF2 interacts directly with certain other mammalian diaphanous formin proteins (mDia) that function as RhoA effector molecules. FSGS-causing INF2 mutations impair these interactions and disrupt the ability of INF2 to regulate Rho/Dia-mediated actin dynamics in vitro. However, the precise mechanisms by which INF2 regulates and INF2 mutations impair glomerular structure and function remain unknown. Here, we characterize an Inf2 R218Q point-mutant (knockin) mouse to help answer these questions. Knockin mice have no significant renal pathology or proteinuria at baseline despite diminished INF2 protein levels. INF2 mutant podocytes do show impaired reversal of protamine sulfate–induced foot process effacement by heparin sulfate perfusion. This is associated with persistent podocyte cytoplasmic aggregation, nephrin phosphorylation, and nephrin and podocin mislocalization, as well as impaired recovery of mDia membrane localization. These changes were partially mimicked in podocyte outgrowth cultures, in which podocytes from knockin mice show altered cellular protrusions compared to those from wild-type mice. Thus, in mice, normal INF2 function is not required for glomerular development but normal INF2 is required for regulation of the actin-based behaviors necessary for response to and/or recovery from injury.
Details
- Title: Subtitle
- Mice with mutant Inf2 show impaired podocyte and slit diaphragm integrity in response to protamine-induced kidney injury
- Creators
- Balajikarthick Subramanian - Beth Israel Deaconess Medical CenterHua Sun - University of IowaPaul Yan - Beth Israel Deaconess Medical CenterVictoria T. Charoonratana - Beth Israel Deaconess Medical CenterHenry N. Higgs - Dartmouth CollegeFang Wang - Peking University First HospitalKa-Man V. Lai - RegeneronDavid M. Valenzuela - RegeneronElizabeth J. Brown - Beth Israel Deaconess Medical CenterJohannes S. Schlöndorff - Beth Israel Deaconess Medical CenterMartin R. Pollak - Beth Israel Deaconess Medical Center
- Resource Type
- Journal article
- Publication Details
- Kidney international, Vol.90(2), pp.363-372
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.kint.2016.04.020
- PMID
- 27350175
- PMCID
- PMC5363079
- ISSN
- 0085-2538
- eISSN
- 1523-1755
- Language
- English
- Date published
- 08/01/2016
- Academic Unit
- Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics
- Record Identifier
- 9984383267002771
Metrics
8 Record Views