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.
Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease in the US. However current regimen provides only partial therapeutic effects and the incidence and prevalence of DKD remains high, suggesting that the key pathogenic mechanisms driving DKD progression are not adequately inhibited by current treatments. Therefore, better understanding of mechanisms that mediate the early stage of DKD and drive the disease progression is urgently required to identify novel preventive and therapeutic measures for DKD patients.
|Hong, Quan; Zhang, Lu; Das, Bhaskar et al. (2018) Increased podocyte Sirtuin-1 function attenuates diabetic kidney injury. Kidney Int 93:1330-1343|
|Liu, Ruijie; Das, Bhaskar; Xiao, Wenzhen et al. (2017) A Novel Inhibitor of Homeodomain Interacting Protein Kinase 2 Mitigates Kidney Fibrosis through Inhibition of the TGF-?1/Smad3 Pathway. J Am Soc Nephrol 28:2133-2143|
|He, Li; Fan, Ying; Xiao, Wenzhen et al. (2017) Febuxostat attenuates ER stress mediated kidney injury in a rat model of hyperuricemic nephropathy. Oncotarget 8:111295-111308|
|Fan, Ying; Zhang, Jing; Xiao, Wenzhen et al. (2017) Rtn1a-Mediated Endoplasmic Reticulum Stress in Podocyte Injury and Diabetic Nephropathy. Sci Rep 7:323|
|Fan, Ying; Xiao, Wenzhen; Lee, Kyung et al. (2017) Inhibition of Reticulon-1A-Mediated Endoplasmic Reticulum Stress in Early AKI Attenuates Renal Fibrosis Development. J Am Soc Nephrol 28:2007-2021|
|Fu, Jia; Wei, Chengguo; Lee, Kyung et al. (2016) Comparison of Glomerular and Podocyte mRNA Profiles in Streptozotocin-Induced Diabetes. J Am Soc Nephrol 27:1006-14|
|Zhong, Fang; Mallipattu, Sandeep K; Estrada, Chelsea et al. (2016) Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy. Am J Pathol 186:2021-2031|
|Xiao, Wenzhen; Fan, Ying; Wang, Niansong et al. (2016) Knockdown of RTN1A attenuates ER stress and kidney injury in albumin overload-induced nephropathy. Am J Physiol Renal Physiol 310:F409-15|
|Menon, Madhav C; He, John C (2016) Prostaglandin I2 Receptor Agonism for Proteinuria and Diabetes: Good for the Goose and Good for the Gander? Diabetes 65:1149-51|