Chronic Interactions #ExpBio

Apr 01 2015 Published by under EB 2015

A number of disorders plague us as we age. Blood pressure rises with age, and increasingly so do blood glucose levels. Some argue that hypertension is a component of type 2 diabetes, but other times it precedes the hyperglycemia. Clinically, it is often difficult to sort out consequences of hyperglycemia and hypertension in the kidney. This abstract shows us how it can be done.

Interaction of Hypertension and Diabetes in Progressive Nephropathy: Role of ER Stress. Z Wang et al.

This study, from John Hall's group at Mississippi, starts with Goto-Kakizaki (GK) rats that spontaneously develop type 2 diabetes about 6 months of age. At time zero, they placed a telemtry device to measure blood pressure in the aorta of these animals. After a couple of weeks fro recovery and baseline measurements, they then used an abdominal coarctation model to produce systemic hypertension that one kidney gets exposed to, but the other sees low flow and pressure.

Used with permission of authors

Used with permission of authors

A coarctation of the aorta may occur spontaneously during fetal development, resulting in hypertension because the kidneys both see low blood flow. Their efforts to correct that, through increased production of renin and all of its effects, causes hypertension. By creating the narrowing of the aorta between the left and right kidneys (see diagram), the upper right kidney gets exposed to the elevated pressure, while the left kidney senses a reduced pressure. For those of you who have not seen this anatomy in the rat, this surgery is a pretty neat trick.

After two more weeks for recovery and measurements, they then added treatment with tauroursodioxycholic acid (TUDCA), an inhibitor of endoplasmic reticulum (ER in the title) stress. ER stress disorders protein folding and transport within cells, contributing to disease and scarring.

Functional and structural markers of kidney damage were increased in the hypertensive kidney compared to the one that had normal or low pressure, as were markers of ER stress. TUDCA treatment lowered these markers, as well as reducing kidney dysfunction in the hypertension-exposed organ.

This elegant study shows that hypertension may accelerate kidney injury from hyperglycemia, at least in part through ER stress. Now, if you have high blood pressure and diabetes, don't head online to try and buy TUDCA yet. As with all animal models, this one is not quite ready for translation to the bedside. First, the GK rat is not obese, so not a typical type 2 diabetes model. Of course, obesity adds a whole lot more issues to this equation, but also makes surgery in this area more difficult. Second, the "unexposed" kidney is the source of the trouble. It's cranking out renin, and we know that the renin-angiotensin system is active within the kidney as well as systemically. Many of these components can affect the kidney; however, I would expect that to blunt the difference between the kidneys rather than increase it. However, it will be interesting to see if TUDCA proves as effective in models that do not depend on renin activation.

This lovely study does convince us that hypertension interacts with hyperglycemia in the kidney to accelerate kidney damage. It also confirms the role of pressure in ER stress.

Strong Work!

 

 

 

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