TY - JOUR T1 - AMP-Kinase mediates regulation of glomerular volume and podocyte survival JF - bioRxiv DO - 10.1101/2021.05.21.445180 SP - 2021.05.21.445180 AU - Khadija Banu AU - Qisheng Lin AU - John M. Basgen AU - Marina Planoutene AU - Chengguo Wei AU - Anand C. Reghuvaran AU - Felipe Garzon AU - Aitor Garcia AU - Nicholas Chun AU - Arun Cumpelik AU - Hongmei Shi AU - Andrew Santaneusio AU - Weijia Zhang AU - Bhaskar Das AU - Fadi Salem AU - Li Li AU - Lloyd G Cantley AU - Shuta Ishibe AU - Lewis Kaufman AU - Kevin V. Lemley AU - Zhaohui Ni AU - John C. He AU - Barbara Murphy AU - Madhav C. Menon Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/05/23/2021.05.21.445180.abstract N2 - We reported that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease, 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 knockdown mice. Knockdown mice exhibited lower glomerular volume, and less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying Fyn was downstream of Shroom3. Using SHROOM3- or FYN-knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMP-kinase, a negative regulator of anabolism. AMP-Kinase activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMP-Kinase abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMP-Kinase activation. In agreement with this, treatment of glomerular injury models with AMP-Kinase activators restricted glomerular volume, podocytopenia and progression to FSGS. In summary, we demonstrate the important role of AMP-Kinase in glomerular volume regulation and podocyte survival. Our data suggest that AMP-Kinase activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.Competing Interest StatementThe authors have declared no competing interest. ER -