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Abstract
Herein, we report that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without focal segmental glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease (MCD), where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral and 5/6th nephrectomy models in Shroom3-KD mice. Knockdown mice exhibited less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying that Fyn was downstream of Shroom3. Using SHROOM3 or FYN knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMPK, a negative regulator of anabolism. AMPK activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMPK abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMPK activation. In agreement with this, treatment of glomerular injury models with AMPK activators restricted glomerular volume, podocytopenia, and progression to FSGS. Glomerular transcriptomes from MCD biopsies also showed significant enrichment of Fyn inactivation and Ampk activation versus FSGS glomeruli. In summary, we demonstrated the important role of AMPK in glomerular volume regulation and podocyte survival. Our data suggest that AMPK activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.
Highlights
Podocytes are specialized epithelial cells on the urinary side of the glomerular filtration barrier, and podocyte actin cytoskeletal disorganization is near universal with nephrotic syndrome (NS) and visualized as foot process effacement (FPE) [1]
We investigated Vglom in this subset with annotated diagnoses of Focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), or membranous nephropathy (n = 80)
We found that MCD cases (n = 27) had significantly lower mean Vglom than FSGS (n = 38) or membranous nephropathy (n = 15) (Figure 1A)
Summary
Podocytes are specialized epithelial cells on the urinary side of the glomerular filtration barrier, and podocyte actin cytoskeletal disorganization is near universal with nephrotic syndrome (NS) and visualized as foot process effacement (FPE) [1]. Focal segmental glomerulosclerosis (FSGS) causes proteinuria and NS, in which podocytes show diffuse FPE associated with podocyte loss, glomerulosclerosis, and progressive renal failure [2]; minimal change disease (MCD), in spite of diffuse FPE, shows no podocytopenia and low rates of disease progression. Comparing signaling events in MCD podocytes during FPE versus FSGS podocytes could define critical mechanisms that maintain podocyte survival in MCD. Using morphometry in humans and experimental models, FSGS has been associated with larger glomerular volumes (Vglom) and podocyte hypertrophy [3,4,5,6,7,8]. Signals that promoted an “MCD-like” pathology in the setting of podocyte injury and FPE by restricting glomerulomegaly, preventing podocytopenia and progression to FSGS, would be of considerable therapeutic interest in all NS
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