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MicroRNA-30 family members regulate calcium/calcineurin signaling in podocytes
Junnan Wu, … , Shaolin Shi, Zhihong Liu
Junnan Wu, … , Shaolin Shi, Zhihong Liu
Published October 5, 2015
Citation Information: J Clin Invest. 2015;125(11):4091-4106. https://doi.org/10.1172/JCI81061.
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Research Article Nephrology Article has an altmetric score of 6

MicroRNA-30 family members regulate calcium/calcineurin signaling in podocytes

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Abstract

Calcium/calcineurin signaling is critical for normal cellular physiology. Abnormalities in this pathway cause many diseases, including podocytopathy; therefore, understanding the mechanisms that underlie the regulation of calcium/calcineurin signaling is essential. Here, we showed that critical components of calcium/calcineurin signaling, including TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3, are the targets of the microRNA-30 family (miR-30s). We found that these 5 genes are highly expressed as mRNA, but the level of the proteins is low in normal podocytes. Conversely, protein levels were markedly elevated in podocytes from rats treated with puromycin aminonucleoside (PAN) and from patients with focal segmental glomerulosclerosis (FSGS). In both FSGS patients and PAN-treated rats, miR-30s were downregulated in podocytes. In cultured podocytes, PAN or a miR-30 sponge increased TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3 expression; calcium influx; intracellular Ca2+ concentration; and calcineurin activity. Moreover, NFATC3 nuclear translocation, synaptopodin degradation, integrin β3 (ITGB3) activation, and actin fiber loss, which are downstream of calcium/calcineurin signaling, were induced by miR-30 reduction but blocked by the calcineurin inhibitor FK506. Podocyte-specific expression of the miR-30 sponge in mice increased calcium/calcineurin pathway component protein expression and calcineurin activity. The mice developed podocyte foot process effacement and proteinuria, which were prevented by FK506. miR-30s also regulated calcium/calcineurin signaling in cardiomyocytes. Together, our results identify miR-30s as essential regulators of calcium/calcineurin signaling.

Authors

Junnan Wu, Chunxia Zheng, Xiao Wang, Shifeng Yun, Yue Zhao, Lin Liu, Yuqiu Lu, Yuting Ye, Xiaodong Zhu, Changming Zhang, Shaolin Shi, Zhihong Liu

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Figure 10

Characterization of the miR-30 sponge–expressing transgenic (SP+) mice.

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Characterization of the miR-30 sponge–expressing transgenic (SP+) mice.
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(A) The SP+ mice developed significant proteinuria (n = 10). Two-tailed Student’s t test, *P < 0.05. (B) Electron microscopic examination of the kidneys of SP+ mice revealed massive foot process effacement of the podocytes. Representative images from 6 mice in each group are shown. Scale bars: 1 μm. (C) The calcineurin phosphatase assay of the isolated glomeruli demonstrated increased calcineurin activity in the glomeruli of SP+ mice compared with that in control mice (n = 5 each). Two-tailed Student’s t test, *P < 0.05. (D) Immunoblotting of the isolated glomeruli revealed increased expression of calcineurin and decreased expression of SYNPO in the glomeruli of SP+ mice. Parallel gels were run for calcineurin or SYNPO and GAPDH. (E) IHC showing that TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3 protein expression levels were upregulated in the glomeruli of SP+ mice. Original magnification, ×40. Representative images from 6 mice in each group are shown. (F) FK506 reduced proteinuria in SP+ mice (n = 8). Two-way ANOVA, *P < 0.05. (G) Electron microscopic image showing that FK506 abolished podocyte foot process effacement in SP+ mice (n = 4). Quantification of the results is shown on the right. FPW, foot processes width. Scale bars: 1 μm. Two-way ANOVA, *P < 0.05. (H) CsA treatment of SP+ mice significantly reduced proteinuria (n = 8). Two-way ANOVA, *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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