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; pā=ā0.071). 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; pā=ā0.002) 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.