The correlation between hypertension, is a very complexed area of study. Many papers attribute hypertension in diabetes to nephropathy, in capacity of that described above: dysfunction of macula densa cells is also used as an attributing factor. But I will have to agree with you, that it is highly plausible that this mechanism is associated with hypertension in DM. a pubmed article on the association of DM and hypertension made observations that hypertension seemed to increase in cases of IDDM, with the onset of nephron hypofunction. The significance of that paper in this discourse is the sub-type of DM...IDDM without associated metabolic dysfunctions.

Another supportive piece of evidence is the side effect associated with SGLT2 inhibitors like (Forxiga) Dapagliflozin, hypotension.

The only negative arguement in this case is the whether upregulation of these receptors are sustained in these cases, and what effected does desensititzation or saturation of these receptors have on blood sodium level.

I am comfortable with the kidney driving hypertension by classical mechanisms when nephropathy supervenes. I wonder what additional mechanisms come in to play. It seems pretty clear that the hypotension with SGLT2 inhibitors is due to hypovolaemia. I wonder how much salt loss contributes over and above the osmotic diuresis that is an inevitable consequence of the glycosurua?

So one last attempt to kick-start this! Although not my research area I understand the glucose transport by SGLT2 to be sodium dependent? If true the upregulation of SGLT2 in diabetes and proven glucose loading of tubular cells must result also in increased sodium uptake into tubular cells. What happens to this sodium? Is there a mechanism for 're-excretion' into tubular fluid?

The mechanism of action of symporter is coupled to an ATPase which acts to create the ion gradient for the symport of Na and glucose. So the Na is pumped out via the associated ATPase, thus an Na, gradient is established outside the tubular cell. I hope this helps.

Thanks Julien, very helpful. Just to clarify, if the baso-lateral Na/K ATPase is responsible for generation of the Na gradient needed to drive lumenal glucose/Na co-transport then the level of SGLT2 expression should not affect total Na transported, as this is limited by the gradient generated by the ATPase. The rate of transport would be affected. What regulates activity of the ATPase? I'm trying to separate chicken and egg here! In normal physiology first!!

In normal proximal tubular cell, glucose concentration is tightly regulated, firstly the ATPase creates the Na gradient to which glucose enters in the tubular surface. On the basolateral surface, GLUT-2 receptors (Uniport) push glucose into the interstitum. 5% or more of re-absorbed glucose is converted to ATP to drive the ATPase in the tubular cell. The GLUT-2 receptor serves it purpose by creating a downhill glucose gradient and releasing glucose to the interstitum. When glucose enters the cell it is converted to glucose-6-phosphate, by a hexokinase (which works best at low glucose concentrations) as compared to it's pancreatic islet cell cousin (isoform).

Therein lies the issue, in the diabetic patient glucose load is high, often contributing to saturation of the hexokinase, therefore the ATP created via glycolysis, may be reduced. so to answer the guestion: ATP concentration is a major down regulator of the ATPase, also concentrations of K and Na on either side of the basolateral membrane is also a factor. I hope this helps to clarify.

The question is to what extent is tubular damage attributed to glucose loading of the tubular cell. GEP's ( Glycated-end Products) may be attributed to tubular damage as well.

I agree many mechanisms of damage including AGEPs but my question is not about this! I am wondering about hypertension. If Na retention is an important contributor, over and above classical mechanisms in renal disease, then different therapeutic approaches might be important eg diuretics (that should really be called natiuretics) perhaps should be prioritised over other antihypertensive agents. And if this is part of the hypertension in diabetic nephropathy then the blood pressure lowering seen with SGLT2 inhibitors might be a desirable therapeutic effect rather than a side effect? Central to all of this is understanding the effect of upregulation of SGLT2 on total body sodium and the effect of SGLT2 blockade on this?

From the initial question above I assumed that that was your focus and as a practioner and research as well I support you idea fully. I really believe you are on to something from a biochemistry and physiology perspective it is highly possible that your hypothesis is correct I wish you success.

Thanks Julien. I wonder if AstraZeneca have any comments!

I can find out if you like

Would be good to know if any data they can share. Probably not but worth asking! Thank you.

We have discussed this idea in the lab several times, but never reached a clear conclusion. I think it's a very relevant open question. A number of studies have shown hyperreabsorption of Na in proximal tubules in diabetic models, but I'm not aware it has been linked experimentally to hypertension.

Dear Julien and Sebastian: I have posted a new question about SGLT2 inhibitors that I would be interested in your thoughts on. I have caught up with the SGLT2 dependent increase in glomerular pressure in hyperglycaemic states (at least in rodent models) and think this may be more important than seems so far to have been considered. It addresses the question above in part as, as far as I can tell, it is due to increased sodium delivery to the macula dense. Interestingly, although there is plenty of opportunity for sodium regulation to be 'corrected' downstream from the sites of most SGLT2 expression, this would seem to be a 'bottom line' as to whether the proximal effects are important. I guess you guys are aware of this, but I would just be interested in continuing this debate and perhaps attracting some more contributions to the new thread? PS I am now talking to AstraZeneca!

This is one of the questions I just asked and I am yet to get an answer to it. I noticed that high glucose concentration does not significantly induce the upregulation of SGLT-2 expression in HK-2 cells. I am looking for a means to upregulate the expression of this protein for further studies. I was thinking of Na retention as another mechanism looking at the mechanism of action of the protein itself. Could retention of sodium ion upregulate the expression of this protein and if it can, can someone please help with a protocol to do that?

Dear Temitope,

I'm afraid I cannot advise with regard to up regulation of SGLT-2 on HK-2 cells, but other people in this discussion may be able to.  Good luck with your studies!