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 9

Overexpression of SIRPα reverses PAN-induced proteinuria and renal pathological damage through promotion of autophagy.

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Overexpression of SIRPα reverses PAN-induced proteinuria and renal patho...
(A) Western blot analysis of SIRPα in mice administered SIRPα-expressing plasmid (SIRPα plasmid) or control plasmid (CTL plasmid) following PAN treatment. Immunoblots are representative of 3 independently performed experiments. The histogram represents statistical results from 3 independently performed experiments. (B) Detection of RFP-SIRPα in glomerulus. (C) Proteinuria (mg/l) content, within 24 hours, of mice treated with PAN. n = 5 mice of each group. (D) PAS staining of kidney tissue sections in mice treated with PAN. (E) SIRPα-overexpressing mice show less foot process fusion by electron microscopy (open arrowhead indicate fused foot processes); scale bar: 1 μm. Histogram represents quantification of GBM thickness (n = 4). (F) GFP-LC3–positive autophagosomes in mice treated with PAN. The histograms represent relative levels of autophagosomes in each group. Each group had 5 mice, and at least 8 glomeruli were analyzed in each mouse. (G) Accumulation of p62 in mice treated with PAN. (H)Western blot analysis of glomerulus p62 in mice treated with PAN. The histogram represents statistical results from 3 independently performed experiments. Data in A, C, E, F, and H represent mean ± SEM, and P value was analyzed by 2-tailed Student’s t test. Scale bars in B, D, F,and G: 10 μm. *P < 0.05, **P < 0.01.