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Kidney Week

Abstract: FR-PO069

Tubular Epithelial Proliferation Accelerates Tubular Atrophy After Kidney Injury Through Its Contractile Capacity

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Yamashita, Noriyuki, Kyoto Prefectural University of Medicine, Kyoto, Japan
  • Kusaba, Tetsuro, Kyoto Prefectural University of Medicine, Kyoto, Japan
  • Tamagaki, Keiichi, Kyoto Prefectural University of Medicine, Kyoto, Japan

Group or Team Name

  • Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Background

Tubular atrophy is a common pathological finding in kidney fibrosis and is characterized by flattened tubular epithelia surrounded by thickened tubular basement membrane (TBM). After injury, neighboring epithelia exert strong mechanical forces on the area surrounding the damaged site in order to close the wound.We hypothesize that the regeneration of tubular epithelia during repair itself drives the TBM to shrink, resulting in tubular atrophy.

Methods

In order to mimic the mechanical effects of tubular epithelia during repair on the TBM in vitro, tubular epithelial cells (NRK52E) were cultured on a thin floating collagen gel, and its changes by various stimuli were assessed. In in vivo experiments, we performed a clonal analysis of solely labeled tubular epithelia using bigenic mice with the proximal tubule-specific tamoxifen-inducible Cre gene (SLC34a1GCE) and tdTomato reporter gene. We then investigated the role of focal adhesion kinase (FAK), a key molecule in the mechanosensing of focal adhesion and the modulation of actin polymerization, during kidney injury and repair.

Results

An in vitro analysis showed that the active proliferation of NRK52E caused the floating gel to shrink and become thick, similar to the TBM of atrophic tubules. The TGFβ treatment accelerated gel contraction, whereas the inhibition of actin polymerization by a FAK or ROCK inhibitor suppressed it. An in vivo clonal analysis after severe ischemia reperfusion injury (IRI), together with upregulation of TGFβ, showed that tubules containing a larger clone number were more likely to be atrophic and lose terminally differentiated tubular markers. In contrast, tubules containing a large clone number were not atrophic in mild IRI kidneys, and differentiated tubule markers were preserved. Based on the active phosphorylation of FAK in the tubular epithelia and interstitial fibroblasts in IRI kidneys, an in vivo clonal analysis showed that the administration of a low dose of the FAK inhibitor ameliorated the atrophy of tubules with a larger clone size and interstitial fibrosis.

Conclusion

The present in vitro andin vivo results indicate that tubular atrophy after severe kidney injury is associated with the active proliferation of tubular epithelia through its contractile capacity induced by upregulation of TGFβ and subsequent actin polymerization.