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Collagen receptor- and metalloproteinase-dependent hypertensive stress response in mesangial and glomerular endothelial cells

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Abstract

Progressive alteration of the extracellular matrix (ECM) is the characteristic of hypertensive nephropathy (HN). Both mesangial and endothelial cells have the ability to synthesize and degrade ECM components, including collagens through the activation of matrix metalloproteinases (MMPs) in stress conditions, such as in hypertension. On the other hand, hydrogen sulfide (H2S) has been shown to mitigate hypertensive renal matrix remodeling. Surprisingly, whether H2S ameliorates receptor-mediated (urokinase plasminogen activator receptor-associated protein, uPARAP/Endo180) collagen dysregulation in Ang-II hypertension is not clear. The purpose of this study was to determine whether Ang-II alters the expression of Endo180, tissue plasminogen activator (tPA), MMPs, and their tissue inhibitors (TIMPs) leading to the dysregulation of cellular collagen homeostasis and whether H2S mitigates the collagen turnover. Mouse mesangial cells (MCs) and glomerular endothelial cells (MGECs) were treated without or with Ang-II and H2S donor GYY (GYY4137) for 48 h. Cell lysates were analyzed by Western blot and RT-PCR, and cells were analyzed by immunocytochemistry. The results indicated that, while Ang-II differentially expressed MMP-13 and TIMP-1 in MCs and in MGECs, it predominantly decreased tPA, Endo 180, and increased plasminogen activator inhibitor-1 (PAI-1), MMP-14, and collagen IIIA and IV in both the cell types. Interestingly, H2S donor GYY treatment normalized the above changes in both the cell types. We conclude that Ang-II treatment causes ECM remodeling in MCs and MGECs through PAI-1/tPA/Endo180 and MMP/TIMP-dependent collagen remodeling, and H2S treatment mitigates remodeling, in part, by modulating these pathways.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Naira Metreveli for her technical assistance related to cell culture experiments and the acquisition of confocal images. This work was supported in part by National Institutes of Health Grants, DK104653 and DK116591 (to U.S.) and American Heart Association Scientist Development Grant, 15SDG25840013 (to S.P.)

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  1. Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, 40202, USA

    Suravi Majumder, Matthew Amin, Sathnur Pushpakumar & Utpal Sen

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Majumder, S., Amin, M., Pushpakumar, S. et al. Collagen receptor- and metalloproteinase-dependent hypertensive stress response in mesangial and glomerular endothelial cells. Mol Cell Biochem 466, 1–15 (2020). https://doi.org/10.1007/s11010-019-03680-y

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