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

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 1

SIRPα deficiency results in an age-dependent onset of proteinuria, loss of podocytes, and glomerulosclerosis.

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SIRPα deficiency results in an age-dependent onset of proteinuria, loss ...
(A) Albumin/creatinine ratio in Sirpa–/– and WT mice at 3, 6, 12, and 20 months (M). (B) Percentages of albuminuria >300mg/l in 20-month-old WT and Sirpa–/– mice (n = 18 WT and n = 20 Sirpa–/– mice; P value was analyzed by Fisher’s exact test). (C) Histology of WT and Sirpa–/– mice at 3, 6, 12, and 20 months (arrows indicate glomerulosclerosis). The histogram represents statistical analysis of sclerosed glomeruli in 20-month WT and Sirpa–/– mice (n = 7 WT mice and n = 7 Sirpa–/– mice; 10–20 glomeruli of each mouse were analyzed). (D) WT1 immunostaining and quantification of WT1-positive glomerular cells in kidneys from 20 months WT and Sirpa–/– mice (glomeruli from n = 6 WT mice and n = 5 Sirpa–/– mice, were analyzed). Scale bars in C and D: 10 μm. Data in A, C, and D represent mean ± SEM, and P value was analyzed by 2-tailed Student’s t test. **P < 0.01.