Nephroprotective Effects Of Pancreatic Kininogenase And Valsartanon Function And Morphology In Spontaneously Hypertensive Rats

Objective:To study the effect of pancreatic kininogenase and valsartan on renal structure and function in spontaneously hypertensive rat (SHR) and explore the role of kallikrein-kinin system and renin-angiotensin system in the development of hypertension and nephroprotection.Methods:24 36-week-old male SHRs were randomly devided into 4 groups. They were respectively given normal diet without drugs (distilled water, n=6), pancreatic kininogenase (800U . kg-1 . d-1, n=6) , valsartan (30mg . kg-1 . d-1, n=6)and the combination of pancreatic kininogenase and valsartan (800U . kg-1 . d-1+30mg . kg-1. d-1, n=6). Age-matched WKYs (n=6) were given only distilled water as control. The drugs were given by gavage. Systolic blood pressure (SBP) was measured before treatment and after 3 weeks, 6 weeks, 9 weeks and 12weeks of treatment. The levels of serum NO, plasma 6-K-PGF1a and the microalbumin(mALB), beta2-microglobin (β2-MG), N-acetyl-β-D-glucosaminidase (NAG) in urine were assessed. The levels of tissue kallikrein mRNA were detected by RT-PCR. Renal tissues were examined routinely by light and electronic microscopy.Results:1. Before experiment, SBP were higher in SHR groups than those in WKYs (p<0.001). SBP were significantly lower after treatment in pancreatic kininogenase, valsartan and the combinations of pancreatic kininogenase and valsartan groups except the contrast one (p<0.01), especially in valsartan and the combination of pancreatic kininogenase and valsartan group (p<0.05).2. Before experiment, the levels of mALB,β2-MG and NAG in urine were higher in SHR groups than those in WKYs (p<0.05). The excretion of mALB,β2-MG and NAG in urine significantly decreased in the treating groups compared to control group(p<0.01), andβ2-MG , NAG were further lower in the combination of pancreatic kininogenase and valsartan group than in pancreatic kininogenase group (p<0.05).3. There is no difference in the serum Scr, BUN between WKY and SHR groups before experiment(P>0.05). The serum BUN was lower after administration (p<0.05), but the serum Scr kept stable after treatment among treating groups compared to control group (p>0.05).4. The serum NO, plasma 6-K-PGF1a were lower in SHR control group than those in WKYs (p<0.05) after treatment. The levels of serum NO in the treating groups were significantly higher than those in the control after treated with pancreatic kininogenase, valsartan and the combinations of pancreatic kininogenase and valsartan (p<0.05), especially in the combination of pancreatic kininogenase and valsartan group (p<0.01). The levels of plasma 6-K-PGF1a were significantly higher in the treating groups compared to control group (p<0.01).5. The levels of tissue kallikrein mRNA expression in the kidneys in SHR control group were lower than those in WKYs(P<0.01), and significantly increased after administration in the treating groups(p<0.05), and further higher in the combinations of pancreatic kininogenase and valsartan group(p<0.01).6. In comparison with WKY, the changes of ultrastructure in the SHR control group showed that: in the control group of SHR, the antrum of the glomerular capillary became strictured, and the fundus membrane incrassated anomaly. The myelinefigure could be seen in the podocyte compound with hyperplasia in the glomerular. In each treatment groups, the glomerulus and the endothelial cells of the glomerular capillary were approximately normal, except for localized incrassation at the fundus membrance of the individual glomerulus.Conclusions1. The KKS plays an important role in the pathophysiological processes of hypertension in SHR.2. Pancreatic kininogenase reduces SBP of SHR and the extent of mALB,β2-MG and NAG in urine , attenuate functional and structural damage induced by hypertension. NO, PGI2 and tissue kallikrein may be involved in the mechanism concerned.3. Our data suggest that the protective effects of pancreatic kininogenase and angiotensin receptor blocker valsartan on lowering blood pressure and renal damage might be associated with the synergism of KKS and RAS.