Management of hypertension in diabetes is critical for reducing cardiovascular mortality and morbidity. Dietary approaches for controlling high blood pressure have historically focused on sodium. Thus, many guidelines recommend that patients with type 2 diabetes reduce high sodium intake. Nonetheless, the potential benefits of sodium reduction are debatable. The kidney has a crucial role in glucose filtration and reabsorption in addition to its regulation of fluid and electrolyte homeostasis. A key factor linking sodium uptake and glucose transport is the sodium-glucose cotransporter 2 (SGLT2) in renal proximal tubular cells. In hyperglycemic states, the renal proximal tubule raises its capacity to reabsorb glucose and sodium from the proximal tubule in response to hyperglycemia because of increased SGLT2 activity. Selective SGLT2 inhibitors improve glycemic control and slightly lower blood pressure in diabetic patients.
In the past decade, activation of peroxisome proliferator-activated receptors (PPARs) has become a novel effective treatment for cardiometabolic diseases. The kidney differentially expresses all three PPAR subtypes, PPARα, PPARγ and PPARδ. Although PPARγ agonists are widely used to treat type 2 diabetes, sodium and water retention still poses a significant limitation to its clinical application. PPARδ is expressed ubiquitously, including in adipose tissues and the kidney. The activation of PPARδ alleviates dyslipidemia, hyperglycemia, and insulin resistance in rodents of obesity and diabetes. Importantly, PPARδ activation by its agonists exerts renal protective effects in diabetic mice. Furthermore, the PPARδ agonists increased adipose adiponectin expression, which are shown to exert multiple beneficial effects against cardiometabolic disorders. However, it is unknown whether PPARδ can regulate renal sodium handing and glucose transport. We hypothesized that PPARδ participates in sodium transport and glucose reabsorption in the kidney, resulting in improved sodium and glucose homeostasis. Here, we present ample evidence to reveal that adipose PPARδ activation promotes natriuresis and glycosuria in mice on high salt diet, which is associated with SGLT2 inhibition in the renal proximal tubule. Our evidence confirms that adipose PPARδ-mediated adiponectin plays a crucial role in the inhibition of renal SGLT2. We also revealed that under physiological circumstances, high sodium intake-induced natriuresis is impaired in diabetic mice because of increased SGLT2 activity. We further observe that type 2 diabetic patients with uncontrolled hyperglycemia have reduced natriuresis, and plasma adiponectin level is closely related to natriuresis in diabetic patients. Overall, the PPARδ-mediated adiponectin maintains equilibrium between urinary glucose transport and sodium reabsorption through regulation of SGLT2 in the kidney, however, this mechanism is impaired in diabetes.
Diabetes and hypertension are often comorbid in patients. Both clinical trials and experimental studies imply that the excess sodium intake raises cardiometabolic risk. Type 2 diabetic patients are more susceptible to hypertension because of their increased exchangeable sodium and salt sensitivity compared with non-diabetic individuals. High sodium intake leads to insulin resistance and greater glomerular pressure, resulting in high blood pressure and albuminuria in type 2 diabetic patients. Our study shows that high sodium intake reduced body weight and fasting blood glucose level while it increased natriuresis in wild type mice. However, this effect was blunted in adipose-specific PPARδ knockout mice and also in diabetic db/db mice. Furthermore, we demonstrate that long-term high sodium intake specifically stimulates adipose PPARδ expression which is associated with elevating tissue sodium content in mice. These findings suggest that PPARδ participates in the regulation of sodium homeostasis. This effect is strikingly different from that of PPARγ agonists, thiazolidinediones that cause sodium and fluid retention.
Adiponectin is a secreted protein in adipose tissue and its production is stimulated by PPARδ activation. Our study shows that high sodium intake also increased plasma adiponectin level, and its expression in both the perirenal fat and renal cortex. We also showed that adiponectin suppresses SGLT2 expression at the transcriptional level. Reducing sodium retention is a critical issue in the management of diabetic patients. Although diuretics are commonly used to reduce sodium retention, long-term diuretic treatment is associated with higher mortality in diabetic patients with hypertension. We show that renal SGLT2 dysfunction was found in diabetic db/db mice and inhibition of SGLT2 by dapagliflozin lowered natriuresis and glycosuria in these mice. Diabetic patients with uncontrolled hyperglycemia reduced natriuresis compared with well-treated patients. Furthermore, natriuresis was largely influenced by blood glucose level in diabetic patients. This finding suggests that well-controlled hyperglycemia may be more effective to alleviate sodium retention in diabetes regardless of their hypoglycemia drugs used. In addition, we reported before that telmisartan, an angiotensin II receptor blocker (ARB), reduced adipogenesis through activation of adipose PPARδ and improved insulin resistance through stimulation of PPARδ in skeletal muscle of mice (He et al., Hypertension, 2010; Li et al., Diabetes, 2013). ARB is also reported to increase plasma adiponectin level and inhibit renal SGLT2 expression in diabetic rats. Therefore, the potential benefit of ARB in the regulation of sodium and glucose homeostasis warrants further investigation.
In summary, we reveal a previously unrecognized role of adipose PPARδ activation-induced natriuresis in mice. Our mechanistic study suggests that this renal benefit is associated with adiponectin-mediated inhibition of renal SGLT2. However, this pathway for maintaining appropriate sodium metabolism in response to high sodium intake is impaired in diabetes, and this defect might result in hyperglycemia-induced sodium retention. We also show that maintaining euglycemia status is a critical factor influencing natriuresis. Our findings provide insights into the physiological role of the PPARδ/adiponectin/SGLT2 pathway in the regulation of sodium and glucose homeostasis. Activation of PPARδ through promotion of adiponectin may represent a promising tool in the management of hypertensive diabetic patients who are exposed to high sodium intake.
Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, China