A Renal-Cerebral-Peripheral Sympathetic Reflex Promotes Salt-Induced Insulin Resistance in Chronic Kidney Disease

Insulin resistance (IR) complicates chronic kidney disease (CKD) by unknown mechanisms. Since we reported that a high-salt intake in CKD activates a renal-cerebral sympathetic reflex, we tested the hypothesis that a high-salt intake in CKD activates a broader reflex response from the kidneys and the white adipose tissue to impair peripheral glucose uptake. High-salt intake in 5/6-nephrectomized rats decreased insulin-stimulated 2-deoxyglucose uptake over 25% in white adipose tissue and skeletal muscle. This depended on a sympathetic nervous system (SNS) reflex that linked the IR to reactive oxygen species (ROS) and the renin-angiotensin system (RAS) in brain nuclei and peripheral tissues. High-salt intake in CKD caused inflammation in adipose tissue and skeletal muscle, and impaired insulin signaling and Glut4 trafficking that were improved by blockade of the central SNS or adrenergic receptors. Denervation of the kidneys or adipose tissue or deafferentation of adipose tissue improved insulin sensitivity similarly by approximately 40%. Furthermore, in a cohort of 100 non-diabetic patients with stage 3-5 CKD, IR was positively correlated with the salt intake after controlling for cofounders (r=0.32, P=0.002). In these patients, IR was also linked to activation of RAS/SNS and impaired glucose uptake in adipose tissue and skeletal muscle that all depended on salt intake. Thus, high-salt intake in CKD initiates afferent signals from the kidneys and adipose tissue that engage a renal-cerebral-peripheral sympathetic reflex that activates the RAS/ROS axes to promote IR via local inflammation and impaired insulin signaling. Funding: This study was supported the National Key Technology Support Program of China (2013BAI09B06; 2015BAI2B07), the State Key Program of National Natural Science Foundation of China (81430016), the Major International (Regional) Joint Research Project of National Natural Science Foundation of China (81620108003), the Foundation for Innovation Research Groups of the National Natural Science Foundation of China (81521003), the National Natural Science Foundation of China (81570619), the Major Scientific and Technological Planning Project of Guangzhou (15020010), NIH (HL-68686; HL-134511; DK-049870; DK-036079) and funds from the George E. Schreiner Chair of Nephrology, the Smith-Kogard and Gildenhorn-Spiesman Family Foundation and the Georgetown University Hypertension Research Center. Declaration of Interests: None. Ethics Approval Statement: All animal experiments were approved by the Institutional Animal Ethics Committee (No. NFYY-2014-05). Human studies were proved by the Nanfang Hospital Ethics Committee (No. NFEC-2015-085).