HYPERTENSION AND DIABETES: THE CHICKEN AND EGG PROBLEM

According to the Centers for Disease Control and Prevention, 29 million Americans had diabetes and 86 million adults were prediabetic in 2014. If the current trend continues, it is predicted that 1 in 3 U.S.adults could have diabetes by 2050. Hypertension often affects people with type 2 diabetes and the combination of diabetes and hypertension is associated with high morbidity and mortality because it leads to cardiovascular and kidney disease^1,2.

In this issue of the Hypertension, Wang and colleagues explored interactions of hypertension and diabetes, and their contribution to kidney injury³. This study is highly significant from both conceptual and technical perspectives. Most of the available animal models for studies of diabetes have other cardiovascular complications. Typically, these animals, as is the case in the human condition, exhibit increased blood pressure (BP) and diabetes in the same model, which makes it impossible to determine whether the renal injury is a consequence of hyperglycemia or is more determined by the elevation of renal perfusion pressure in the hypertensive state. The authors developed a novel experimental model, which allowed them to study the mechanisms of kidney injury in diabetes under the condition of normal and elevated BP. Hypertension to one kidney was induced either in diabetic Goto-Kakizaki (GK) or control Wistar rat by aorta constriction (AC) between the renal arteries. Therefore, both kidneys were exposed to the same levels of hyperglycemia, circulating hormones, neural activity and other factors but the right kidney above the AC was exposed to elevated BP compared to the left kidney below the AC.

Using this approach, the authors compared the kidney function and level of injury in GK rats in diabetic only (left, below the AC) and diabetic hypertensive (right, above the AC) kidneys (Figure 1). It was reported that after 4 weeks of AC, glomerular filtration rate (GFR) in the right kidney of GK-AC rats was higher than in the left kidney. However, after 8 weeks of AC, GFR in the right kidney declined substantially compared to the 4^th week, which indicates that combined hypertension and diabetes in the right kidney cause an initial increase in GFR followed by a decline to normal within 4 weeks, associated with assessed increased urinary albumin excretion. Furthermore, a significantly higher renal injury score and glomerular ultra-structural changes were found in the right kidneys of GK-AC rats compared to the left kidneys of GK-AC rats. Eight weeks of moderate hypertension induced by AC in control Wistar rats caused only modest albuminuria, endoplasmic reticulum (ER) stress and oxidative stress, and did not increase the renal injury score. Therefore, major effects on glomerular hyperfiltration, albuminuria, and kidney injury were only observed when hyperglycemia was combined with hypertension. There is a possibility that hyperglycemia impairs renal autoregulation, which leads to pressure-dependent glomerular hyperfiltration, ER stress and kidney injury. Whether this injury is caused solely by the synergistic effects of hyperglycemia and increased BP to cause glomerular hyperfiltration, or by other mechanisms related to increased intraglomerular pressure is still unclear.

Figure 1.

Schematic of the developed approach and proposed synergistic effects of diabetes and hypertension on the kidney (adopted from³). As shown in this figure, increased blood pressure (BP) followed aorta constriction (AC) in non-diabetic kidney and normal BP in diabetic kidneys conditions result in mild kidney injury. Both hyperglycemia (high glucose; HG) and high BP required to develop severe kidney injury.

Importantly, the authors provided some mechanistic insight toward hypertension and diabetes interaction by uncovering the role of ER stress. It is reported that the ER stress marker C/EBP homologous protein (CHOP) was markedly increased in the right kidneys of GK-AC rats. Chronic administration of tauroursodeoxycholic acid (TUDCA), the ER stress inhibitor, decreased albumin excretion and the glomerular injury score while attenuating the decline in GFR in kidneys of GK-AC rats. Thus, this study provided additional knowledge about this critical pathway. However, it is clear that ER stress is not the only single mechanim involved in the studied relationship between diabetes and hypertension. Therefore, the established approach should be further applied to uncover and test additional pathways. As an example, increased level of reactive oxygen species is reported for both hypertension and diabetes and is likely to play a role in this synergism^4,5. In fact, Wang et al. reported increased expression of 4-HNE, an indicator of lipid peroxidation and oxidative stress, in the hypertensive kidneys of GK-AC rats.

Briefly, these data demonstrate the synergistic interaction of diabetes and hypertension in promoting kidney injury since the effect of hyperglycemia and the effect of hypertension alone on kidney injury was minimal. A few questions raise from the current study. First, this study still does not address “which came first: the chicken or the egg?” question and it is unclear whether hyperglycemia is causative of high BP, or maybe hypertension is instrumental for diabetes development. However, it is obvious that hyperglycemia and hypertension are synergistic with regards to kidney injury. One of the limitations (or advantages on the other hand) of this study is that GK rats were used here. The GK rat is a well-established model of spontaneous type 2 diabetes, generated by selecting and inbreeding hyperglycemic Wistar rats. However, in these rats signs of diabetic nephropathy (DN) become apparent only with age, unless hypertension is induced by administration of DOCA and a high salt diet⁶. It would be interesting to see if the same phenotype is observed in the T2DN model that was developed by crossing GK and Fawn-Hooded Hypertensive (FHH)⁷ rats or some other models of DN⁸ where animals have some degree of prehypertension. Another question is relevant to technical limitations of the described method. While it is clear that the developed approach has some advantages, such as a relatively simple surgical preparation, does not require special equipment and can be used for a long time (up to 8 weeks in current study), it has certain limitations. For instance, as shown in the manuscript, although a BP gradient above and below AC was established in GK-AC and Wistar–AC rats, there is a fixed constrictor around the aorta. This means as hypertension developed in the rat, the BP rose both above and below the AC. Immediately upon placement of the aortic constrictor, the perfusion pressure to the kidney below the AC would be reduced for some time until BP above the AC would rise to some undefined level, probably within the normal range. BP was measured (using telemetry) during the entire protocol only above the right kidney, and the BP gradient was assessed only on the last day of experiment, under anesthesia, when femoral artery catheterization was performed. Perfusion pressure to the left kidney could therefore have been either lower or even somewhat higher than normal during the long experimental period, and it unclear what occurred during the progression of the experiment.

In conclusion, with the given caveats this study by Wang et al. implicates a key role for the synergistic interaction of mild diabetes and hypertension in regulation of renal function and promoting kidney injury. There has been significant controversy during the past decade about what is appropriate BP control to optimally reduce cardiovascular and kidney disease-related events in patients with diabetes⁹. Described here manuscript is in line with the clinical studies, which indicate that it is important to keep BP in diabetic patients under tight control. Importantly, this study is one of the first steps towards the understanding of the interaction of hypertension and diabetes, and it emphasizes the need for further investigation of this important area.