Friday, May 9, 2025
5/9/2025
Importance of cell-matrix interactions in kidney repair after acute kidney injury - PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI) is characterized by abrupt deterioration in kidney function, manifested by an increase in serum creatinine level, with or without a reduction in the amount of urine output. Tragically, between 2009- 2019, hospitalizations in the US complicated by AKI increased by 42%. The long-term objectives of this application are to better understand the kidney local microenvironment and its impact on AKI with an eye towards development of new treatment strategies. The AKI research field believes that renal tubules are the epicenter of damage, yet little attention has been paid to changes in the renal local microenvironment and associated repair processes, which are certain to impact AKI. The concept of a ‘microenvironment’ has shaped the understanding of the pathogenesis of various diseases. However, the AKI microenvironment is poorly characterized. The kidney local microenvironment in AKI - consisting of injured tubular cells, activated fibroblasts, inflammatory cells (e.g., macrophages), other cellular components, extracellular matrix (ECM), and a variety of secreted factors - is complex, heterotypic, and dynamic. After AKI, in general, renal tubules undergo a repair process of dedifferentiation. During this process, ECM is the major organizing component for microenvironment construction and tubule repair, serving as a scaffold for remodeling. The major cellular source of ECM synthesis in the kidney is interstitial fibroblasts. Several subpopulations of fibroblasts are activated exceptionally early after AKI (1h), far earlier than tubular cell proliferation (3d). This suggests that fibroblast-derived proteins may act early in AKI. To explore this idea in depth, matrix proteins were compared between AKI and control kidneys using ischemic kidney models and proteomics. This identified extracellular matrix protein 1 (ECM1; a secreted glycoprotein) as the earliest and highest activated matrix protein after ischemic AKI. ECM1 was induced rapidly (4-8h) after AKI and localized predominantly to fibroblast-rich foci in the kidney interstitium. It was also found that after AKI, Sonic Hedgehog (Shh) growth factor secreted by renal tubules specifically targets fibroblasts to mediate cell-matrix interactions. Further study revealed that ECM1 binds to Shh in vitro, knockdown of ECM1 aggravates AKI in vivo, and ECM1 peptide prevents tubular cell death in vitro. Based on these observations and the role of macrophages in microenvironment formation, it was hypothesized that after AKI, ECM1 directly recruits Shh, which activates fibroblasts and macrophages to form a favorable microenvironment to promote kidney remodeling. This hypothesis will be tested by determining the mechanistic role of ECM1 in kidney microenvironment formation ex vivo (Aim 1); determining the roles of injured tubules, activated fibroblasts, and macrophages in constructing the kidney microenvironment after AKI (Aim 2); and determining the role of the ECM1-organized cell-matrix interactions in promoting AKI repair in vivo (Aim 3). Our investigations have broad implications for elucidating mechanisms for kidney repair and designing novel therapeutic regimens to prevent or mitigate AKI.
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