Signal regulatory protein α protects podocytes through promotion of autophagic activity
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
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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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 7

SIRPα critically controls podocyte stress adaptation through promotion of autophagy in vivo.

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SIRPα critically controls podocyte stress adaptation through promotion o...
(A) GFP-LC3–positive autophagosomes in GFP-LC3–transgenic mice (GFP-LC3) and Sirpa–/– mice crossed with GFP-LC3-transgenic mice (Sirpa–/–GFP-LC3, with proteinuria, 20 months). Arrows indicate autophagosomes. The histogram represents statistical autophagosomes in each group. n = 5 each group of mice and 6–10 glomeruli from each mouse were analyzed. (B) Accumulation of the ubiquitin-associated protein p62 in 20-month-old GFP-LC3 and Sirpa–/–GFP-LC3 mice (arrows indicate podocytes). (C) Western blot analysis of p62 in glomerulus of 20-month-old GFP-LC3 and Sirpa–/–GFP-LC3 mice. Immunoblots are representative of 3 independently performed experiments. The histogram represents statistical results from 3 independently performed experiments. (D) GFP-LC3–positive autophagosomes in 8-week-old GFP-LC3–transgenic mice and Sirpa–/–GFP-LC3 mice treated with PAN, ADR, or STZ; arrows indicate autophagosomes. The histograms represent statistical autophagosomes in each group. n = 3 each group of mice and 10 glomeruli from each mouse were analyzed. (E) Accumulation of p62 in 8-week-old GFP-LC3 and Sirpa–/–GFP-LC3 mice treated with PAN for 2 weeks (2W), ADR for 4 weeks, and STZ for 6 weeks (arrows indicate podocytes). (F) Western blotting of p62 in glomerulus of 8-week-old GFP-LC3 and Sirpa–/–GFP-LC3 mice with different treatments. Immunoblots are representative of 3 independently performed experiments. The histogram represents statistical results from 3 independently performed experiments. Scale bars in A, B, D, and E: 10 μm. Data in A, C, D, and F represent mean ± SEM, and P values were analyzed by 2-tailed Student’s t test. *P < 0.05, **P < 0.01.