Albuminuria enhances NHE3 and NCC via stimulation of mitochondrial oxidative stress/angiotensin II axis

// Zhanjun Jia 1, 2, * , Yibo Zhuang 1, 2, * , Caiyu Hu 1, 2 , Xintong Zhang 3 , Guixia Ding 1, 2 , Yue Zhang 1, 2 , Rajeev Rohatgi 4 , Hu Hua 1, 2 , Songming Huang 1, 2 , John Ci-jiang He 5 , Aihua Zhang 1, 2 1 Department of Nephrology, Nanjing Children’s Hospital, Affiliated with Nanjing Medical University, Nanjing, China 2 Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China 3 The First Clinical Medical College of Nanjing Medical University, Nanjing, China 4 Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA 5 Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA * These authors contributed equally to this work Correspondence to: Aihua Zhang, email: zhaihua@njmu.edu.cn John Ci-jiang He, email: cijiang.he@mssm.edu Keywords: albuminuria, NHE3, NCC, mitochondrial oxidative stress, angiotensin II Received: October 30, 2015      Accepted: May 20, 2016      Published: June 13, 2016 ABSTRACT Imbalance of salt and water is a frequent and challenging complication of kidney disease, whose pathogenic mechanisms remain elusive. Employing an albumin overload mouse model, we discovered that albuminuria enhanced the expression of NHE3 and NCC but not other transporters in murine kidney in line with the stimulation of angiotensinogen (AGT)/angiotensin converting enzyme (ACE)/angiotensin (Ang) II cascade. In primary cultures of renal tubular cells, albumin directly stimulated AGT/ACE/Ang II and upregulated NHE3 and NCC expression. Blocking Ang II production with an ACE inhibitor normalized the upregulation of NHE3 and NCC in cells. Interestingly, albumin overload significantly reduced mitochondrial superoxide dismutase (SOD2), and administration of a SOD2 mimic (MnTBAP) normalized the expression of NHE3, NCC, and the components of AGT/ACE pathway affected by albuminuria, indicating a key role of mitochondria-derived oxidative stress in modulating renin-angiotensin system (RAS) and renal sodium transporters. In addition, the functional data showing the reduced urinary excretion of Na and Cl and enhanced response to specific NCC inhibitor further supported the regulatory results of sodium transporters following albumin overload. More importantly, the upregulation of NHE3 and NCC and activation of ACE/Ang II signaling pathway were also observed in albuminuric patient kidneys, suggesting that our animal model accurately replicates the human condition. Taken together, these novel findings demonstrated that albuminuria is of importance in resetting renal salt handling via mitochondrial oxidative stress-initiated stimulation of ACE/Ang II cascade. This may also offer novel, effective therapeutic targets for dealing with salt and water imbalance in proteinuric renal diseases.