Abstract
The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN), is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patients who do not adequately respond to angiotensin receptor blocker (ARB) treatment. Novel approaches include the stimulation of soluble guanylate cyclase (sGC) as it is reported to have beneficial effects on cardiac and renal damage. We aimed to investigate the effects of the sGC stimulator riociguat and ARB telmisartan on kidney function and structure in a hypertensive model of diabetic nephropathy.Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1 mg/kg/d), riociguat (3 mg/kg/d), riociguat+telmisartan (3+1 mg/kg/d), and vehicle. Fourteen mice were used as non-diabetic controls. Treatment duration was 11 weeks.Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9 mmHg compared with diabetic controls (111.2±2.3 mmHg vs. 117.1±2.2 mmHg; p = 0.071). Treatment with riociguat both alone and in combination with telmisartan led to a significant reduction of blood pressure towards diabetic vehicle (105.2±2.5 mmHg and 105.0±3.2 mmHg, respectively, vs. 117.1±2.2 mmHg). Combined treatment also significantly decreased albuminuria compared with diabetic controls (47.3±9.6 µg/24 h vs. 170.8±34.2 µg/24 h; p = 0.002) reaching levels similar to those of non-diabetic controls (34.4±10.6 µg/24 h), whereas the reduction by single treatment with either telmisartan (97.8±26.4 µg/24 h) or riociguat (97.1±15.7 µg/24 h) was not statistically significant. The combination treatment led to a significant (p<0.01) decrease of tissue immunoreactivity of malondialdehyde, as consequence of reduced oxidative stress.In conclusion, stimulation of sGC significantly reduced urinary albumin excretion in diabetic eNOS knockout mice treated already with ARB. Thus, this new drug class on top of standard ARBs administration may offer a new therapeutic approach for patients resistant to ARB treatment.
Highlights
Worldwide prevalence of diabetes mellitus features increasing numbers medical consequences such as diabetic retinopathy, neuropathy and nephropathy extend as well
There are a number of patients who do not adequately respond to this gold standard therapy with respect to blood pressure reduction and reduction of urinary albumin excretion, and the need for treatment improvement is highest in those patients
In contrast final blood pressure measurements revealed that riociguat alone and in combination with telmisartan significantly reduced blood pressure in comparison to diabetic control mice (p = 0.002 and p = 0.004, respectively), whereas administration of telmisartan alone led to a fairly modest and non-significant reduction of blood pressure (p = 0.071)
Summary
Worldwide prevalence of diabetes mellitus features increasing numbers medical consequences such as diabetic retinopathy, neuropathy and nephropathy extend as well. Prevention of progressive diabetic nephropathy (DN) includes control of hyperglycaemia and blood pressure as well as additional nephroprotection such as inhibition of the renin-angiotensin-aldosterone system (RAAS) [4,5,6,7]. Telmisartan, which is an angiotensin receptor II blocker (ARB), has proven to be very effective at reducing transition rates to overt nephropathy [8] and increasing nitric oxide (NO) activity of the renal endothelium in patients with diabetes mellitus type 2 (T2DM) [6,9]. There are a number of patients who do not adequately respond to this gold standard therapy with respect to blood pressure reduction and reduction of urinary albumin excretion, and the need for treatment improvement is highest in those patients. An animal model that resembles this clinical situation is the diabetic endothelial NO synthase (eNOS) knockout mouse [10,11,12]
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