Effects of stimulation of soluble guanylate cyclase on diabetic nephropathy in diabetic eNOS knockout mice on top of angiotensin II receptor blockade

PLoS One. 2012;7(8):e42623. doi: 10.1371/journal.pone.0042623. Epub 2012 Aug 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / administration & dosage
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Animals
  • Benzimidazoles / administration & dosage
  • Benzimidazoles / pharmacology
  • Benzoates / administration & dosage
  • Benzoates / pharmacology
  • Biomarkers / blood
  • Blood Glucose / drug effects
  • Blood Pressure / drug effects
  • Diabetic Nephropathies / drug therapy
  • Diabetic Nephropathies / genetics*
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / mortality
  • Disease Models, Animal
  • Guanylate Cyclase / antagonists & inhibitors
  • Guanylate Cyclase / metabolism*
  • Kidney Function Tests
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide Synthase Type III / genetics*
  • Nitric Oxide Synthase Type III / metabolism
  • Organ Size / drug effects
  • Pyrazoles / administration & dosage
  • Pyrazoles / pharmacology
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology
  • Receptors, Angiotensin / metabolism*
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Soluble Guanylyl Cyclase
  • Telmisartan

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Benzimidazoles
  • Benzoates
  • Biomarkers
  • Blood Glucose
  • Pyrazoles
  • Pyrimidines
  • Receptors, Angiotensin
  • Receptors, Cytoplasmic and Nuclear
  • Nitric Oxide Synthase Type III
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase
  • riociguat
  • Telmisartan

Grant support

This study was supported by Bayer HealthCare AG, Wuppertal, Germany (http://www.wuppertal.bayer.de/). The work of Dr. Alter was supported by a grant from the Dr. Werner Jackstädt- Stiftung (http://www.jackstaedt-stiftung.de/). No additional external funding received for this study. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.