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Signal regulatory protein α protects podocytes through promotion of autophagic activity
Limin Li, … , Zhihong Liu, Ke Zen
Limin Li, … , Zhihong Liu, Ke Zen
Published May 2, 2019; First published March 19, 2019
Citation Information: JCI Insight. 2019;4(9):e124747. https://doi.org/10.1172/jci.insight.124747.
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Categories: Research Article Nephrology

Signal regulatory protein α protects podocytes through promotion of autophagic activity

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Abstract

High autophagic activity in podocytes, terminally differentiated cells that serve as main components of the kidney filtration barrier, is essential for podocyte survival under various challenges. How podocytes maintain such a high level of autophagy, however, remains unclear. Here we report that signal regulatory protein α (SIRPα) plays a key role in promoting podocyte autophagy. Unlike other glomerular cells, podocytes strongly expressed SIRPα, which was, however, downregulated in patients with focal segmental glomerulosclerosis and mice with experimental nephropathy. Podocyte SIRPα levels were inversely correlated with the severity of podocyte injury and proteinuria but positively with autophagy. Compared with WT littermates, Sirpa-deficient mice displayed greater age-related podocyte injury and proteinuria and developed more rapid and severe renal injury in various models of experimental nephropathy. Mechanistically, podocyte SIRPα strongly reduced Akt/GSK-3β/β-catenin signaling, leading to an increase in autophagic activity. Our findings thus demonstrate a critical protective role of SIRPα in podocyte survival via maintenance of autophagic activity.

Authors

Limin Li, Ying Liu, Shan Li, Rong Yang, Caihong Zeng, Weiwei Rong, Hongwei Liang, Mingchao Zhang, Xiaodong Zhu, Koby Kidder, Yuan Liu, Zhihong Liu, Ke Zen

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Figure 5

Sirpa–/– mice develop more rapid and severe renal injury in various models of nephropathy.

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Sirpa–/– mice develop more rapid and severe renal injury in various mod...
(A) Albumin/creatinine ratio (mg/mg) in WT and Sirpa–/– mice with ADR, PAN, and STZ treatment (n = 5 WT and n = 5 Sirpa–/– mice). (B) ADR, PAN, and STZ injection in Sirpa–/– mice resulted in glomerulosclerosis by PAS staining (arrows); scale bar: 50 μm. Histogram represents quantification of glomerulosclerosis (5 WT and Sirpa–/– mice of each group; 10–20 glomeruli of each mouse were analyzed). (C) ADR, PAN, and STZ injection in Sirpa–/– mice results in more severe foot process fusion by electron microscopy (arrows indicate fused foot processes); scale bars: 1 μm. Histogram represents quantification of GBM thickness (glomeruli from 4 WT and 3 Sirpa–/– mice were analyzed). (D) ADR, PAN, and STZ injection in Sirpa–/– mice results in severe loss of podocytes (n = 5 WT and n = 5 Sirpa–/– mice; 5–6 glomeruli for each mouse were analyzed). Scale bar: 25 μm. (E) Fluorescence staining of F-actin using phalloidin in human podocytes (HPC) transfected with SIRPα-expressing plasmid. Scale bar: 25 μm. Quantification of fiber formation was performed by counting approximately 60 podocytes from 3 independent determinations. Data in A–E represent mean ± SEM, and P value was analyzed by 2-tailed Student’s t test. *P < 0.05, **P < 0.01.
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