Diabetic nephropathy (DN) is associated with hypertension, urinary plasmin excretion and ability of urine to activate epithelial sodium channel (ENaC) current in vitro. It was hypothesized that deletion of plasminogen and amiloride treatment protects against hypertension in diabetes. Male plasminogen knockout (plg-/-) and wild-type mice were rendered diabetic by streptozotocin injections. After 4 weeks, urine was analyzed for albumin, plasmin(ogen) and the effect on current in collecting duct cells by patch clamp. Arterial blood pressure was recorded continuously by chronic indwelling catheters for 10 days (8 days ANGII-30-60 ng/kgxmin). Albuminuria was more pronounced in diabetic plg-/- compared to diabetic wildtype. Immunoblotting showed plasminogen in plasma from wildtype mice only and in urine from diabetic wildtype mice only. Baseline mean arterial blood pressure did not differ between groups and while ANGII induced hypertension in wildtype, diabetic wildtype and plg -/- control mice, this response was abolished in diabetic plg-/- In ongoing studies, amiloride treatment for 3 days (n=4) in wildtype ANGII-hypertensive diabetic mice showed a tendency to counteract hypertension compared to ANGII infusion alone (n=2). Urine from diabetic and control wildtype mice evoked significantly larger amiloride-sensitive current than urine from diabetic and control plg-/- mice. Gamma ENaC displayed marked proteolysis in all 4 groups after ANGII infusion with no difference in abundance. No statistical significant difference between groups was found in kidney tissue protein level of prorenin receptor, TLR4 or TGFβ. Results indicated no change in infiltration of TH17 cells. In Plg-/- there was reduced infiltration of CD45-positive leukocytes. In summary, disruption of plasminogen in diabetic mice is associated with increased albuminuria, similar baseline blood pressure, but protection from ANGII-induced hypertension. In conclusion, plasmin promotes hypertension in diabetes with albuminuria compatible with an action through aberrant filtration.
Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB370
Poster Communications: Plasminogen deficiency attenuates angiotensin II-induced hypertension in diabetic mice
M. H. Hansen1, H. Andersen1, K. Buhl1, M. Stæhr1, U. Friis1, P. Svenningsen1, C. Enggaard1, I. Lund2, S. Supramaniyam1, P. Lærkegaard Hansen1, B. L. Jensen1
1. Cardio-vascular and renal research, University of Southern Denmark, Odense, Denmark. 2. University of Copenhagen, Copenhagen, Denmark.
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