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

Detailed transmission electron microscopy analysis of glomeruli in SIRPα–deficient mice.

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Detailed transmission electron microscopy analysis of glomeruli in SIRPα...
(A) Transmission electron microscopy (TEM) of foot process fusion and effacement of podocytes and the glomerular basement membrane (GBM) (podocytes of n = 4 WT mice and n = 3 Sirpa–/– mice were analyzed). Open arrowheads, foot process fusion; filled arrowheads, foot process effacement; filled arrows, vacuoles. Histograms represent quantification of foot process fusion, effacement of podocytes, and GBM thickness. (B) TEM of the glomerulus of 6-, 12-, and 20-month-old WT and Sirpa–/– mice. Open black arrowheads, microvillus; open red arrowheads, regular rough ER; filled red arrowheads, distension of rough ER; open red stars, regular mitochondria; filled red stars, damaged mitochondria. Histograms represent quantification of microvillus formation, distension of rough ER, and damaged mitochondria in WT versus Sirpa–/– mice. (podocytes of n = 4 WT mice and n = 3 Sirpa–/– mice were analyzed). (C) Lipofuscin accumulation in 6-, 12-, and 20-month-old Sirpa–/– mice (podocytes of n = 4 WT mice and n = 3 Sirpa–/– mice were analyzed). Arrows indicate lipofuscin aggregates. The histogram represents statistical analysis of lipofuscin aggregates. Scale bars: 1 μm. Data represent the mean ± SEM, and P value was analyzed by 2-tailed Student’s t test. *P < 0.05, **P < 0.01.