Publication Date

2015-06-08

Availability

Open access

Embargo Period

2015-06-09

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cell Biology and Anatomy (Medicine)

Date of Defense

2015-05-15

First Committee Member

Christian H. Faul

Second Committee Member

Pedro Salas

Third Committee Member

Barry Hudson

Fourth Committee Member

Alessia Fornoni

Abstract

Aberrant elevation in cytoplasmic calcium levels in podocytes cause changes in podocyte morphology and glomerular permeability. The phosphatase calcineurin responds to elevated calcium by dephosphorylating the nuclear factor of activated T-cells (NFAT). We have shown that podocyte-specific activation of NFAT in transgenic mice causes rapid proteinuria. Transgenic mice with the podocyte-specific, doxycyclin (Dox)-inducible expression of constitutively active NFAT (NFATc1nuc) were fed Dox chow, and urine albumin levels were monitored. Mice were sacrificed at different time points for histological studies of the kidney, including H&E, TEM analysis of the podocyte foot process (FP) structure and WT1 labeling to determine podocyte numbers. Dox was removed at 2 months to study a potential reversibility of the phenotype. NFATc1nuc mice are proteinuric within four days of Dox exposure with podocyte FP effacement. NFATc1nuc induction for two months causes sustained proteinuria with an increase in FP effacement, but without other histological changes within the kidney. Animals on Dox treatment for 10 months develop glomerular sclerosis, extraglomerular lesions and impaired renal function. Proteinuria in mice with short-term NFATc1nuc activation in podocytes is reversible, whereas mice with NFATc1nuc expression for two months are unable to revert to normal podocyte morphology and kidney function. Podocyte-specific NFAT activation in mice causes a two-phase renal phenotype. First reversible MCD-like alterations, followed irreversible FSGS-like changes. These changes happen in the setting of progressive podocyte loss. This phenotypic switch from a MCD-to an FSGS-like phenotype may also occur in concert with changes in the responsiveness to pharmacological interventions.

Keywords

NFAT; FSGS; Minimal Change Disease; Chronic Kidney Disease; podocyte

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