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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. May 15, 2015; 6(4): 576-582
Published online May 15, 2015. doi: 10.4239/wjd.v6.i4.576
How the kidney hyperfiltrates in diabetes: From molecules to hemodynamics
Tsuneo Takenaka, Tsutomu Inoue, Yusuke Watanabe
Tsuneo Takenaka, Department of Medicine, International University of Health and Welfare, Tokyo 107-0052, Japan
Tsuneo Takenaka, Department of Medicine, International University of Health and Welfare, Clinical Research Center, Sanno Hospital, Tokyo 107-0052, Japan
Tsutomu Inoue, Yusuke Watanabe, Department of Nephrology, Saitama Medical University, Iruma Saitama 350-0495, Japan
Author contributions: Takenaka T designed the studies and wrote the manuscript; Inoue T and Watanabe Y performed most of the experiments and statistical analyses.
Conflict-of-interest: All authors have no conflicts of interests to declare regarding this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Tsuneo Takenaka, MD, PhD, Professor, Department of Medicine, International University of Health and Welfare, Clinical Research Center, Sanno Hospital, 8-10-16 Akasaka Minato, Tokyo 107-0052, Japan. takenaka@iuhw.ac.jp
Telephone: +81-3-34023301 Fax: +81-3-34043652
Received: May 23, 2014
Peer-review started: May 24, 2014
First decision: July 10, 2014
Revised: January 26, 2015
Accepted: February 4, 2015
Article in press: February 9, 2015
Published online: May 15, 2015
Processing time: 357 Days and 5.5 Hours
Abstract

In this review, we focused on two molecules, connexin and sodium-glucose cotransporter, which can link to diabetic hyperfiltration. In diabetic kidney, the activation of renin-angiotensin system occurs simultaneously with glomerular hyperfiltration. The latter largely depends on pathophysiological afferent arteriolar dilation in the presence of high angiotensin II. As a mechanistic basis for the above, tubular hypothesis has been proposed for type 1 diabetic patients as well as experimental models. Although tubular hypothesis has not been well evaluated in type 2 diabetes, clinical observations support that tubular hypothesis is true also in type 2 diabetes. Recent results on tubular hypothesis along with connexin abnormality in type 2 diabetes were revisited. In addition, the importance of sodium-glucose cotransporter in diabetic hyperfiltration is discussed. The link between salt paradox and the activation of renin-angiotensin system will be also reviewed.

Keywords: Tubuloglomerular feedback; Salt paradox; Connexin; Glomerular hyperfiltration; Sodium-glucose co-transporter

Core tip: A diminished tubuloglomerular feedback (TGF) in diabetes can explain both glomerular hyperfiltration and the activation of renin-angiotensin system. An enhanced absorption through sodium-glucose co-transporter in proximal tubule decreases the delivery to macula densa, reducing TGF signal generation in diabetes. Connexin phosphorylation and subsequent ubiquitination by oxidative stress in type 2 diabetes reduces its expression in juxtaglomerular apparatus, disabling TGF signal transduction. Clinical as well as experimental evidences support that this tubular hypothesis is working, and suggest that drugs targeting the above to normalize TGF, an intrinsic physiological system, would be effective to ameliorate diabetic nephropathy.