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Kidney Week

Abstract: FR-OR18

RTNA1 Mediates the Diabetic Kidney Disease Progression Through Endoplasmic Reticulum (ER) Mitochondrial Contacts in Renal Tubular Epithelial Cells

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Zhong, Fang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background

Renal tubular epithelial cell (RTEC) injury contributes to kidney fibrosis and the progression of diabetic kidney disease (DKD), but the major risk factors contributing to RTEC injury in early DKD remain unclear. We previously showed that expression of reticulon 1A (RTN1A), an ER-associated protein, increases in RTEC in human and mice with DKD and contributes RTEC injury in vitro and in vivo through activation of ER stress. Here, we will further dissect the role and mechanism of RTA1A in RTEC injury in early DKD.

Methods

To assess the RTEC-specific role of RTN1A in the progression of DKD, we generated transgenic mice with tetracycline-inducible, RTEC-specific RTN1A overexpression (Pax8-rtTA;TRE-RTN1A). To assess the role of RTN1A in tubular injury in the setting of DKD, diabetes was induced in 8-week old transgenic mice with low-dose injections of streptozotocin (STZ). Also, we crossed the Pax8-RTN1A mice with diabetic OVE26. To delineate the molecular mechanisms of RTN1A-induced RTEC injury, we examined the RTN1A-interacting proteins by mass spectrometry. The role of RTN1A in regulation of ER-mitochondrial contacts (EMC) was assessed by measurement of both mitochondrial function and ER stress markers in the cultured RTEC and mice with RTN1A overexpression.

Results

We found that increased RTN1A expression in the RTEC induced significantly tubule-interstitial fibrosis and decline of renal function in both STZ and OVE26 diabetic mice with early DKD. We also demonstrated in vitro that RTN1A interacted with several mitochondrial proteins and RTN1A was enriched in the EMC. We showed that RTN1A overexpression in RTECs not only worsens ER stress but also induces mitochondrial dysfunction in RTEC in vitro and in vivo. As a novel mechnanism, we demonstrated that RTN1A interacts with mitochondrial hexokinase-1 (HK1) and competing for its interaction with voltage-dependent anion channel-1 (VDAC1). Disengagement of VDAC1 from HK1 subsequently results in the activation of apoptosis and inflammasome pathways, leading to RTEC injury and loss.

Conclusion

Our findings highlight the previously unrecognized role of ER-mitochondrial crosstalk in RTEC injury and progression of DKD and the importance of RTN1A-mediated EMC regulation in DKD pathogenesis.

Funding

  • NIDDK Support