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Kidney Week

Abstract: SA-PO106

The Tubular Epithelial Role of SMOC2 in Aristolochic Acid Nephropathy

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Gao, Peng, Universite de Montreal Departement de Pharmacologie et Physiologie, Montreal, Quebec, Canada
  • Barrera-Chimal, Jonatan, Hopital Maisonneuve-Rosemont Centre de Recherche, Montreal, Quebec, Canada
  • Henley, Nathalie, Hopital Maisonneuve-Rosemont Centre de Recherche, Montreal, Quebec, Canada
  • Gerarduzzi, Casimiro, Universite de Montreal Departement de Pharmacologie et Physiologie, Montreal, Quebec, Canada
Background

Acute kidney injury (AKI) is a prevalent clinical condition with a rising incidence, posing an increased risk of chronic kidney disease (CKD) development characterized by interstitial fibrosis. Our lab has previously shown the effects of the matricellular protein SMOC2 on fibroblasts in regard to renal fibrosis present within CKD patients and in vivo kidney models. However, its involvement in tubular epithelial cell injury during AKI and its transition into CKD has not been previously examined.

Methods

Wild-type and SMOC2 knock-out (KO) mice were subjected to aristolochic acid I (AAI) injection to induce nephrotoxic AKI (known as aristolochic acid nephropathy, AAN). To evaluate the underlying mechanism, bulk RNAseq analysis of WT and KO kidneys 3 days after AAI injection was performed. Primary mouse tubular epithelial cells (mTECs) and human proximal tubular epithelial cells (HK-2) were exposed to recombinant SMOC2 (rSMOC2) protein alone or in combination with AAI.

Results

SMOC2 expression was increased in AAI-treated mTECs and renal tubules in AAI-injected mice, which was accompanied with tubular injury. On day 3 after injection, SMOC2 KO kidneys had increased tubular necrosis and histological damage scores compared to WT AAI-injected mice. Bulk RNAseq analysis revealed an increased expression of proliferation-related genes (CCND1 and Mki67) in SMOC2 KO AKI mice. In vitro studies showed that rSMOC2 treatment alone did not affect the proliferation of HK-2 cells; however, when combined with AAI treatment, it induced complete cell cycle arrest.

Conclusion

In contrast to the proliferative role of SMOC2 in fibroblasts during renal fibrosis, we unexpectedly discovered a cell cycle arrest role of SMOC2 on TECs. SMOC2 deficiency accelerates tubular cell proliferation after AKI, which renders them vulnerable to cell death signals. Therefore, SMOC2 may be a novel and important modulator of cellular injury after AKI by assisting in cell cycle arrest, which allows more time for DNA damage to be repaired, thus preventing the proliferation of cells with genotoxic insults and potentially avoiding maladaptive epithelial responses to injury.

Funding

  • Government Support – Non-U.S.