Plasminogen Deficiency and Amiloride Mitigate Angiotensin II–Induced Hypertension in Type 1 Diabetic Mice Suggesting Effects Through the Epithelial Sodium Channel

Abstract

Background Diabetic nephropathy is a common diabetes mellitus complication associated with hypertension, proteinuria, and excretion of urinary plasmin that activates the epithelial sodium channel, ENaC, in vitro . Here we hypothesized that the deletion of plasminogen and amiloride treatment protect against hypertension in diabetes mellitus. Methods and Results Male plasminogen knockout (plasminogen‐deficient [Plg −/− ]) and wild‐type mice were rendered diabetic with streptozotocin. Arterial blood pressure was recorded continuously by indwelling catheters before and during 10 days of angiotensin II infusion (ANGII; 30–60 ng/kg per minute). The effect of amiloride infusion (2 mg/kg per day, 4 days) was tested in wild‐type, diabetic ANGII‐treated mice. Streptozotocin increased plasma and urine glucose concentrations and 24‐hour urine albumin and plasminogen excretion. Diabetic Plg −/− mice displayed larger baseline albuminuria and absence of urine plasminogen. Baseline mean arterial blood pressure did not differ between groups. Although ANGII elevated blood pressure in wild‐type, diabetic wild‐type, and Plg −/− control mice, ANGII did not change blood pressure in diabetic Plg −/− mice. Compared with ANGII infusion alone, wild‐type ANGII‐infused diabetic mice showed blood pressure reduction upon amiloride treatment. There was no difference in plasma renin, ANGII, aldosterone, tissue prorenin receptor, renal inflammation, and fibrosis between groups. Urine from wild‐type mice evoked larger amiloride‐sensitive current than urine from Plg −/− mice with or without diabetes mellitus. Full‐length γ‐ENaC and α‐ENaC subunit abundances were not changed in kidney homogenates, but the 70 kDa γ‐ENaC cleavage product was increased in diabetic versus nondiabetic mice. Conclusions Plasmin promotes hypertension in diabetes mellitus with albuminuria likely through the epithelial sodium channel.

Endothelial mineralocorticoid receptor ablation confers protection towards endothelial dysfunction in experimental diabetes in mice

“…We have previously shown that ECMR‐KO mice do not have elevated blood pressure at baseline or following AngII infusion compared to WT 25 . Furthermore, STZ‐diabetic control mice on a FVB background have no change in blood pressure compared to healthy controls in the 5th week of diabetes by 24h invasive measurements in freely moving unstressed mice 42 . As a result of the uncompensated diabetes with hyperglycemia, glucosuria and 4‐6 times increased diuresis on the FVB background, 42 mice are likely to exhibit extracellular volume contraction which would fit with reactive stimulation of aldosterone secretion and the observed elevated level in plasma.…”

“…25 Furthermore, STZ-diabetic control mice on a FVB background have no change in blood pressure compared to healthy controls in the 5th week of diabetes by 24h invasive measurements in freely moving unstressed mice. 42 As a result of the uncompensated diabetes with hyperglycemia, glucosuria and 4-6 times increased diuresis on the FVB background, 42 mice are likely to exhibit extracellular volume contraction which would fit with reactive stimulation of aldosterone secretion and the observed elevated level in plasma. It is therefore less likely that blood pressure is increased in the present ECMR-KO mice as also observed previously in mouse STZ-diabetes models.…”

Kir4.1 deletion prevents salt-sensitive hypertension in early streptozotocin-induced diabetic mice via Na+–Cl− cotransporter in the distal convoluted tubule

“…Several lines of evidence indicate that increased ENaC activity contributes to the development of HS or angiotensin II-induced hypertension [45][46][47][48]. Recently, Andersen et al found that plasminogen deficiency protects against angiotensin II-induced hypertension in type 1 diabetic mice, and this effect was likely mediated by ENaC [21]. Previous studies have demonstrated that the expression of ENaC subunit was increased in hyperglycemic animals [25,26,49]; however, most of these results were observed in rat models.…”

“…Randomly selected 8-10 weeks old male WT and Ks-Kir4.1 KO mice received five consecutive days of streptozotocin (Sigma-Aldrich, St Louis, Missouri, USA) injection (i.p.) at 55 mg/kg per day under fasting conditions, whereas mice with the same age and genetic background receiving vehicle (sodium citrate, pH 4.5) were used as controls, as described previously [21]. Two weeks after STZ injection, mice were prepared for experiments by monitoring fasting blood glucose (FBG > 16.7 mmol/l), measured using a glucometer (OneTouch).…”

Dissection of the potential anti‐diabetes mechanism of salvianolic acid B by metabolite profiling and network pharmacology

“…Plasminogen (PLG) is correlated with diabetes along with hypertension. 29 Meanwhile, angiotensin I converting enzyme (ACE)…”