bay-41-8543 and Ureteral-Obstruction

Gender difference and nitric oxide deficiency contribute to the progression of many chronic kidney diseases. In a model of unilateral ureteral obstruction relief we analyzed the impact of biological gender and nitric oxide/cyclic guanosine monophosphate signaling stimulation on renal disease severity and restoration.. Female and male rats underwent sham surgery or unilateral ureteral obstruction. After 5-day unilateral ureteral obstruction female and male rats were assigned to obstruction relief alone or obstruction relief plus 7-day treatment with the soluble guanylate cyclase stimulator BAY 41-8543.. Compared to male rats with obstruction relief renal disease was less severe in female rats, which had significantly less tubulointerstitial matrix accumulation and tubular atrophy. In each gender group α1 and β1-soluble guanylate cyclase was comparably and significantly increased but female rats produced significantly more cyclic guanosine monophosphate after treatment with the soluble guanylate cyclase stimulator. In each group BAY 41-8543 treatment was associated with significant amelioration of renal matrix protein expansion, macrophage infiltration, tubular apoptosis and atrophy.. Female gender is protective for unilateral ureteral obstruction relief. This was linked to higher sensitivity of the soluble guanylate cyclase enzyme and cyclic guanosine monophosphate production in response to BAY 41-8543. In these female and male rats enhancing the signaling of nitric oxide/cyclic guanosine monophosphate with BAY 41-8543 significantly accelerated the restoration of renal architecture after obstruction relief and largely ameliorated the differences in disease severity due to the gender disparity.

Topics: Administration, Oral; Animals; Apoptosis; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Guanylate Cyclase; In Situ Nick-End Labeling; Kidney; Male; Morpholines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Recovery of Function; RNA, Messenger; Severity of Illness Index; Sex Factors; Soluble Guanylyl Cyclase; Treatment Outcome; Ureteral Obstruction

The antifibrotic effects of soluble guanylate cyclase stimulation and cyclic guanosine monophosphate production have been observed in cases of anti-thy1-induced renal disease. We analyzed the action of the specific soluble guanylate cyclase stimulator BAY 41-8543 on the renal recovery phase in rats with unilateral ureteral obstruction after obstruction was relieved.. Sprague-Dawley® rats underwent reversible unilateral ureteral obstruction for 5 days, after which obstruction was relieved. Rats were randomly assigned to unilateral ureteral obstruction and unilateral ureteral obstruction plus BAY 41-8543 (10 mg/kg body weight daily). Seven days after relief of obstruction we determined treatment effects on renal atrophy, apoptosis, fibrosis and nitric oxide/cyclic guanosine monophosphate signaling.. Untreated obstructed rats showed mildly increased systolic blood pressure, marked tubular atrophy and apoptosis, tubulointerstitial macrophage infiltration and fibrosis. Plasma cyclic guanosine monophosphate levels were unaltered in untreated rats with obstruction while renal soluble guanylate cyclase mRNA expression was increased. BAY 41-8543 administration significantly increased plasma cyclic guanosine monophosphate, which was paralleled by significant decreases in systolic blood pressure, renal tubular diameter, apoptosis and renal macrophage infiltration. Also, soluble guanylate cyclase stimulation decreased tubulointerstitial fibrosis, as shown by tubulointerstitial volume, matrix protein accumulation, α-smooth muscle actin expression, collagen IV deposition and transforming growth factor-β1 mRNA expression.. Soluble guanylate cyclase stimulation by BAY 41-8543 increases cyclic guanosine monophosphate production and subsequently enhances renal recovery after unilateral ureteral obstruction relief through an array of pathways. This finding suggests that soluble guanylate cyclase stimulation may serve as a novel treatment approach to restore or preserve renal structure and function in cases of obstructive kidney disease.

Topics: Animals; Guanylate Cyclase; Kidney; Male; Morpholines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Recovery of Function; Soluble Guanylyl Cyclase; Ureteral Obstruction