Published online May 15, 2015. doi: 10.4239/wjd.v6.i4.576
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
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.
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.