Abstract
Acute kidney injury (AKI) is common and associated with significant morbidity and mortality. Recovery from many forms of AKI involves the proliferation of renal proximal tubular epithelial cells (RPTECs), but the influence of the microenvironment in which this recovery occurs remains poorly understood. Here we report the development of a poly(ethylene glycol) (PEG) hydrogel platform to study the influence of substrate mechanical properties on the proliferation of human RPTECs as a model for recovery from AKI. PEG diacrylate based hydrogels were generated with orthogonal control of mechanics and cell-substrate interactions. Using this platform, we found that increased substrate stiffness promotes RPTEC spreading and proliferation. RPTECs showed similar degrees of apoptosis and Yes-associated protein (YAP) nuclear localization regardless of stiffness, suggesting these were not key mediators of the effect. However, focal adhesion formation, cytoskeletal organization, focal adhesion kinase (FAK) activation, and extracellular signal-regulated kinase (ERK) activation were all enhanced with increasing substrate stiffness. Inhibition of ERK activation substantially attenuated the effect of stiffness on proliferation. In long-term culture, hydrogel stiffness promoted the formation of more complete epithelial monolayers with tight junctions, cell polarity, and an organized basement membrane. These data suggest that increased stiffness potentially may have beneficial consequences for the renal tubular epithelium during recovery from AKI.
Highlights
Acute kidney injury (AKI) is common, costly, and associated with increased mortality [1,2,3]
Because others have shown a tight correlation between bulk hydrogel properties and the mechanics of thin hydrogel films [27], we measured the rheological properties of bulk hydrogel slabs after simulated surface modification
We report an in vitro model using a biocompatible scaffold system with human renal proximal tubular epithelial cells (RPTECs) to explore the role of Extracellular matrix (ECM) stiffness in recovery from acute kidney injury
Summary
Acute kidney injury (AKI) is common, costly, and associated with increased mortality [1,2,3]. Interstitial fibrosis is the final common pathway in most forms of CKD and is associated with a worse prognosis [5]. Use of magnetic resonance and sonographic techniques to measure tissue mechanical properties as a surrogate for fibrosis is attracting interest as a noninvasive diagnostic approach in renal transplants [6] and other organs [7]. Using these types of imaging techniques, it has been observed that even patients with relatively mild CKD have increased stiffness of the renal parenchyma [8,9]. How this increased parenchymal stiffness might impact recovery from AKI remains poorly understood
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