NO-independent activation of soluble guanylate cyclase prevents disease progression in rats with 5/6 nephrectomy

Abstract

1. Chronic renal disease is associated with oxidative stress, reduced nitric oxide (NO) availability and soluble guanylate cyclase (sGC) dysfunction. Recently, we discovered BAY 58-2667, a compound activating heme-deficient or oxidized sGC in a NO-independent manner. 2. We assessed potential of BAY 58-2667 in preventing cardiac and renal target organ damage in rats with 5/6 nephrectomy. 3. Male Wistar rats were allocated to three groups: 5/6 nephrectomy, 5/6 nephrectomy treated with BAY 58-2667 and sham operation. Study period was 18 weeks: blood pressure and creatinine clearance were assessed repeatedly. At study end blood samples were taken and hearts and kidneys harvested for histological studies. 4. BAY 58-2667 markedly lowered blood pressure in animals with 5/6 nephrectomy (untreated versus treated animals: 189+/-14 versus 146+/-11 mmHg, P<0.001). Left ventricular weight, cardiac myocyte diameter as well as cardiac arterial wall thickness significantly decreased in comparison to untreated animals with 5/6 nephrectomy. Natriuretic peptide plasma levels were also improved by BAY 58-2667. Kidney function and morphology as assessed by creatinine clearance, glomerulosclerosis, interstitial and perivascular fibrosis of intrarenal arteries were likewise significantly improved by BAY 58-2667. 5. This is the first study showing that BAY 58-2667 effectively lowers blood pressure, reduces left ventricular hypertrophy and slows renal disease progression in rats with 5/6 nephrectomy by targeting mainly oxidized sGC. Therefore, BAY 58-2667 represents a novel pharmacological principle with potential clinical value in treatment of chronic renal disease.

Figure 1

Creatinine clearance. All values are given as mean±s.d. ^**P<0.001 versus sham OP. ^†P<0.05 versus 5/6 NX.

Figure 2

Systolic blood pressure. All values are given as mean±s.d.. ^**P<0.001 versus sham OP. ^‡P<0.001 versus 5/6 NX.

Figure 3

Relative left cardiac ventricle weight. All values are given as mean±s.d.. ^*P<0.05 versus sham OP. ^†P<0.05 versus 5/6 NX.

Figure 4

Typical sections of heart and kidney. (a) 5/6 NX; (b) 5/6 NX+BAY 58-2667; (c) sham OP. First column: typical cardiac arteries in Elastica-van Gieson staining, Magnitude × 200. Second column: typical kidney sections in PAS staining, Magnitude × 200. Presence of PAS-positive material (pink color) within glomeruli indicates glomerulosclerosis. Third column: typical kidney sections in Sirius-Red-staining, Magnitude × 200. Red color indicates fibrotic areas.