# Role of RTN1A in the Progression of Diabetic Nephropathy

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $451,535

## Abstract

Project Summary
Diabetic kidney disease (DKD) remains as the leading cause of ESRD in USA and the treatment options are
limited. Therefore, it is critical for us to identify contributing factors for the progression of DKD. By analyzing the
transcriptomic datasets in mouse models with different rates of disease progression, we identified Reticulon-1
(Rtn1), a gene encoding an endoplasmic reticulum (ER)-associated protein, as a risk factor for progression of
CKD. We found that RTN1A expression is markedly increased in the diseased kidney and inversely correlated
with eGFR in human with DKD. In vitro, we showed that RTN1A mediates ER stress and apoptosis in renal
tubular epithelial cells (RTEC). In vivo, we showed that a global knockdown of Rtn1a expression attenuated
albuminuria and kidney injury in streptozotocin (STZ)-induced diabetic mice. During the last funding period, we
further demonstrated that the induction of RTN1A expression in RTEC in the STZ-induced diabetic mice
resulted in the decline of renal function and development of renal fibrosis, which are not typically observed in
STZ-induced diabetic mice. Screening of RTN1A-interacting proteins surprisingly showed that the highly
ranked proteins were mitochondrial proteins, such as hexokinase 1 (HK1), TOMM40, and SLC25A12.
Consistent with this, a recent study also demonstrates a large amount of RTN1A in the ER-mitochondrial
contact sites. ER-mitochondrial contact (EMC), or also referred as mitochondria-associated ER membranes
(MAMs), have pleiotropic effects on a variety of intracellular events including mitochondrial damage, Ca2+
signaling, ER stress, apoptosis, and autophagy. However, the direct association of EMC with kidney disease
has not been reported. Our preliminary data showed that overexpression of RTN1A in HK2 cells induced not
only ER stress but also mitochondrial dysfunction. High glucose increased both ER stress and mitochondrial
dysfunction in HK2 cells, which was further aggravated by RTN1A overexpression. In vivo, diabetic mice with
RTN1A overexpression in RTEC had increased markers for both ER stress and mitochondrial dysfunction.
These data suggest a critical role of RTN1A in mediating both ER stress and mitochondrial dysfunction likely
through EMC. Also, we confirmed that RTN1A interacted with HK1 and induced the degradation of HK1 in
RTEC and HK1 is a key regulator of apoptosis and inflammasome activation. Based on these data, we
hypothesize that RTN1A-mediated EMC plays a critical role in inducing tubular cell injury and the progression
of DKD. To test this, we propose to determine 1) the role of RTN1A in mediating EMC in RTEC injury in
diabetic condition; 2) the mechanism of RTN1A-mediated EMC in RTEC injury in diabetic condition; and 3) the
potential interventions to regulate EMC as a therapy for DKD.

## Key facts

- **NIH application ID:** 10144990
- **Project number:** 5R01DK109683-06
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** John Cijiang He
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $451,535
- **Award type:** 5
- **Project period:** 2016-04-18 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144990

## Citation

> US National Institutes of Health, RePORTER application 10144990, Role of RTN1A in the Progression of Diabetic Nephropathy (5R01DK109683-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10144990. Licensed CC0.

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