Sonic hedgehog connects podocyte injury to mesangial activation and glomerulosclerosis
Dong Zhou, … , Donna B. Stolz, Youhua Liu
Dong Zhou, … , Donna B. Stolz, Youhua Liu
Published October 10, 2019
Citation Information: JCI Insight. 2019;4(22):e130515. https://doi.org/10.1172/jci.insight.130515.
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Research Article Nephrology

Sonic hedgehog connects podocyte injury to mesangial activation and glomerulosclerosis

Abstract

Glomerular disease is characterized by proteinuria and glomerulosclerosis, two pathologic features caused by podocyte injury and mesangial cell activation, respectively. However, whether these two events are linked remains elusive. Here, we report that sonic hedgehog (Shh) is the mediator that connects podocyte damage to mesangial activation and glomerulosclerosis. Shh was induced in glomerular podocytes in various models of proteinuric chronic kidney diseases (CKD). However, mesangial cells in the glomeruli, but not podocytes, responded to hedgehog ligand. In vitro, Shh was induced in podocytes after injury and selectively promoted mesangial cell activation and proliferation. In a miniorgan culture of isolated glomeruli, Shh promoted mesangial activation but did not affect the integrity of podocytes. Podocyte-specific ablation of Shh in vivo exhibited no effect on proteinuria after adriamycin injection but hampered mesangial activation and glomerulosclerosis. Consistently, pharmacologic blockade of Shh signaling decoupled proteinuria from glomerulosclerosis. In humans, Shh was upregulated in glomerular podocytes in patients with CKD and its circulating level was associated with glomerulosclerosis but not proteinuria. These studies demonstrate that Shh mechanistically links podocyte injury to mesangial activation in the pathogenesis of glomerular diseases. Our findings also illustrate a crucial role for podocyte-mesangial communication in connecting proteinuria to glomerulosclerosis.

Authors

Dong Zhou, Haiyan Fu, Yang Han, Lu Zhang, Shijia Liu, Lin Lin, Donna B. Stolz, Youhua Liu

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Figure 7

Blockade Shh signaling attenuates glomerulosclerosis in diabetic kidney disease.

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Blockade Shh signaling attenuates glomerulosclerosis in diabetic kidney ...
(A) Urinary albumin levels of db/db mice at different time points after CPN treatment. *P < 0.05 versus lean mice (n = 3–4, Student-Newman-Keuls test). (B and C) qPCR showed that CPN did not significantly affect podocyte-specific genes, such as nephrin, podocin, and CD2AP (B) but inhibited numerous fibrosis-related genes, including fibronectin, collagen I, and α-SMA (C). *P < 0.05 versus lean mice; †P < 0.05 versus vehicle (n = 3–4, Student-Newman-Keuls test). (D and E) Western blot analysis showed that CPN has little effect on podocyte-specific α-actinin-4 expression in db/db mice, but it inhibited α-SMA, PDGFR-β, and β-catenin expression at 2 weeks after CPN treatment. Representative Western blot (D) and quantitative data (E) are presented. *P < 0.05 versus lean mice, †P < 0.05 versus vehicle, Student-Newman-Keuls test. (F) Representative micrographs reveal that CPN inhibited glomerular PDGFR-β and α-SMA expression but did not affect nephrin. Arrows indicate nephrin expression, while arrowheads denote PDGFR-β+ and α-SMA+ staining. Scale bar: 25 μm. (G–I) Quantitative determination of nephrin (G), PDGFR-β (H), and α-SMA (I) staining in the glomeruli of different groups of mice as indicated. *P < 0.05 versus lean mice; †P < 0.05 versus vehicle, Student-Newman-Keuls test. (J) Representative micrographs revealed that CPN attenuated glomerulosclerosis in db/db mice. Kidney sections were subjected to periodic acid–Schiff (PAS), PAS-methenamine (PASM), and Mason’s trichrome staining (MTS), respectively. (K) Quantitative determination of glomerulosclerosis in different groups of mice as indicated. *P < 0.05 versus lean mice; †P < 0.05 versus vehicle, Student-Newman-Keuls test.