The British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
J Physiol. 2019 Feb;597(3):767-780. doi: 10.1113/JP277332. Epub 2018 Dec 23.
Type 1 diabetes mellitus increases cardiovascular risk; hypertension amplifies this risk, while pressure natriuresis regulates long-term blood pressure. We induced type 1 diabetes in rats by streptozotocin injection and demonstrated a substantial impairment of pressure natriuresis: acute increases in blood pressure did not increase renal medullary blood flow, tubular sodium reabsorption was not downregulated, and proximal tubule sodium reabsorption, measured by lithium clearance, was unaffected. Insulin reduced blood glucose in diabetic rats, and rescued the pressure natriuresis response without influencing lithium clearance, but did not restore medullary blood flow. Radiotelemetry showed that diastolic blood pressure was increased in diabetic rats, and its diurnal variation was reduced. Increases in medullary blood flow and decreases in distal tubule sodium reabsorption that offset acute rises in BP are impaired in early type 1 diabetes, and this impairment could be a target for preventing hypertension in type 1 diabetes.
Type 1 diabetes mellitus (T1DM) substantially increases cardiovascular risk, and hypertension amplifies this risk. Blood pressure (BP) and body sodium homeostasis are linked. T1DM patients have increased total exchangeable sodium, correlating directly with BP. Pressure natriuresis is an important physiological regulator of BP. We hypothesised that pressure natriuresis would be impaired, and BP increased, in the early phase of T1DM. Male Sprague-Dawley rats were injected with streptozotocin (30-45 mg/kg) or citrate vehicle. After 3 weeks, pressure natriuresis was induced by serial arterial ligation. In non-diabetic controls, this increased fractional excretion of sodium from ∼1% to ∼25% of the filtered load (P < 0.01); in T1DM rats, the response was significantly blunted, peaking at only ∼3% (P < 0.01). Mechanistically, normal lithium clearance suggested that distal tubule sodium reabsorption was not downregulated with increased BP in T1DM rats. The pressure dependence of renal medullary perfusion, considered a key factor in the integrated response, was abolished. Insulin therapy rescued the natriuretic response in diabetic rats, restoring normal downregulation of tubular sodium reabsorption when BP was increased. However, the pressure dependence of medullary perfusion was not restored, suggesting persistent vascular dysfunction despite glycaemic control. Radiotelemetry showed that T1DM did not affect systolic BP, but mean diastolic BP was ∼5 mmHg higher than in non-diabetic controls (P < 0.01), and normal diurnal variation was reduced. In conclusion, functional impairment of renal sodium and BP homeostasis is an early manifestation of T1DM, preceding hypertension and nephropathy. Early intervention to restore pressure natriuresis in T1DM may complement reductions in cardiovascular risk achieved with glycaemic control.
1 型糖尿病会增加心血管风险；高血压会放大这种风险，而压力利钠则调节长期血压。我们通过链脲佐菌素注射诱导大鼠 1 型糖尿病，并证实压力利钠显著受损：急性血压升高不会增加肾髓质血流量，管状钠重吸收没有下调，而通过锂清除测量的近端肾小管钠重吸收不受影响。胰岛素降低了糖尿病大鼠的血糖，并在不影响锂清除的情况下挽救了压力利钠反应，但没有恢复髓质血流量。无线电遥测显示，糖尿病大鼠的舒张压升高，昼夜变化减少。在早期 1 型糖尿病中，抵消急性血压升高的髓质血流量增加和远端肾小管钠重吸收减少受损，这种损伤可能是预防 1 型糖尿病高血压的靶点。
1 型糖尿病（T1DM）会大大增加心血管风险，而高血压会进一步放大这种风险。血压（BP）和体内钠稳态是相关的。T1DM 患者的总可交换钠含量增加，与 BP 直接相关。压力利钠是 BP 的重要生理调节剂。我们假设压力利钠会在 T1DM 的早期阶段受损，BP 升高。雄性 Sprague-Dawley 大鼠注射链脲佐菌素（30-45mg/kg）或柠檬酸载体。3 周后，通过动脉结扎连续诱导压力利钠。在非糖尿病对照组中，这会使钠的分数排泄从过滤负荷的约 1%增加到约 25%（P<0.01）；在 T1DM 大鼠中，反应明显减弱，峰值仅为约 3%（P<0.01）。从机制上讲，正常的锂清除表明在 T1DM 大鼠中，随着 BP 的升高，远端肾小管钠重吸收没有下调。肾髓质灌注的压力依赖性被废除，被认为是综合反应的关键因素。胰岛素治疗挽救了糖尿病大鼠的利钠反应，当 BP 升高时，恢复了正常的管状钠重吸收下调。然而，髓质灌注的压力依赖性没有恢复，这表明尽管血糖得到控制，但血管功能仍持续存在障碍。无线电遥测显示，T1DM 不影响收缩压，但平均舒张压比非糖尿病对照组高约 5mmHg（P<0.01），正常的昼夜变化减少。总之，T1DM 早期即出现肾功能和钠血压稳态的功能障碍，早于高血压和肾病。在 T1DM 中恢复压力利钠的早期干预可能会补充血糖控制所带来的降低心血管风险的效果。
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