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High–molecular weight hyaluronan attenuates tubulointerstitial scarring in kidney injury
Xinyi Wang, … , Jizhong Cheng, Sundeep G. Keswani
Xinyi Wang, … , Jizhong Cheng, Sundeep G. Keswani
Published May 12, 2020
Citation Information: JCI Insight. 2020;5(12):e136345. https://doi.org/10.1172/jci.insight.136345.
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Research Article Nephrology

High–molecular weight hyaluronan attenuates tubulointerstitial scarring in kidney injury

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Abstract

Renal fibrosis features exaggerated inflammation, extracellular matrix (ECM) deposition, and peritubular capillary loss. We previously showed that IL-10 stimulates high–molecular weight hyaluronan (HMW-HA) expression by fibroblasts, and we hypothesize that HMW-HA attenuates renal fibrosis by reducing inflammation and ECM remodeling. We studied the effects of IL-10 overexpression on HA production and scarring in mouse models of unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R) to investigate whether IL-10 antifibrotic effects are HA dependent. C57BL/6J mice were fed with the HA synthesis inhibitor, 4-methylumbelliferone (4-MU), before UUO. We observed that in vivo injury increased intratubular spaces, ECM deposition, and HA expression at day 7 and onward. IL-10 overexpression reduced renal fibrosis in both models, promoted HMW-HA synthesis and stability in UUO, and regulated cell proliferation in I/R. 4-MU inhibited IL-10–driven antifibrotic effects, indicating that HMW-HA is necessary for cytokine-mediated reduction of fibrosis. We also found that IL-10 induces in vitro HMW-HA production by renal fibroblasts via STAT3-dependent upregulation of HA synthase 2. We propose that IL-10–induced HMW-HA synthesis plays cytoprotective and antifibrotic roles in kidney injury, thereby revealing an effective strategy to attenuate renal fibrosis in obstructive and ischemic pathologies.

Authors

Xinyi Wang, Swathi Balaji, Emily H. Steen, Alexander J. Blum, Hui Li, Christina K. Chan, Scott R. Manson, Thomas C. Lu, Meredith M. Rae, Paul F. Austin, Thomas N. Wight, Paul L. Bollyky, Jizhong Cheng, Sundeep G. Keswani

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Figure 3

Increased IL-10 levels in kidney tissues are driven by lenti-GFP-IL-10 transduction.

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Increased IL-10 levels in kidney tissues are driven by lenti-GFP-IL-10 t...
(A) Images of the kidney cortex at day 3 after UUO. Almost no GFP is observed in tissues transduced with control (empty GFP vector) versus strong signal from tissues treated with lenti-GFP-IL-10. Scale bars: 50 μm. (B) Quantification of imaging data was performed by measuring GFP intensity corresponding to immunofluorescence staining. **P < 0.001. (C) Tissue IL-10 concentration (pg/mg tissue weight) from day 3 lenti-GFP (control) UUO or day 3 lenti-GFP-IL-10–treated UUO kidneys was measured by an IL-10 ELISA test kit. **P < 0.001.

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