Role Of Renin Angiotensin System In Aging Kidney And Effects Of Its Long-term Inhibition

Objective To ascertain the change of renin angiotensin system (RAS) expressed in aging kidney, identify the role of RAS in aging related changes, and find out the effect of chronic angiotensin II blockade on aging kidney and gene expressions of angiotensin II receptors. Methods Male Wistar rats were analyzed for their general physical signs, renal function, urine protein, and renal pathological changes during aging. Concentration of renin, angiotensin II, aldosterone, and activity of angiotensin I converting enzyme (ACE) were measured respectively. Genes expression of fibronectin(FN), plasminogen activator inhibitor- 1 (PAI-1), transforming growth factor(TGFpM) ,and angiotensin II receptor(ATiaR) were analyzed by Northern blot, ATlbR and AT2R by RT-PCR. Glomeruli as well as renal tubules and renal arteries were isolated by laser microdissection and pressure catapulting system, ATiaR mRNA, AT1bR mRNA AT2R mRNA were measured with RT-PCR. Fifteen month old rats were divided into 4 groups, receiving fosinopril(5mg/kg), valsartan(25mg/kg), combination therapy respectively for 9 months to 24 month old. The above mentioned indexes were analyzed in each treatment group comparing to the control one. Results Body weight (BW) of rats increased gradually with aging, and kept unchanged after 12-month old, with no obvious changes of kidney /body weight ratio, as well as blood pressure and heart rate in different groups. Comparing to 3-month old rats, 24-month old rats showed a marked decrease in the concentration of plasma albumin, with an increase in the concentration of blood urine nitrogen, leaving serum creatinine, serum urine acid, as well as CO2 combining ability unchanged in each group. Urine protein of rats began to increase after 15 months, and increased greatly at 24 months. Renal pathological changes of 24-month old rats include the expansion of renal glomeruli and accumulation of extracellular matrix (ECM), focal segmental glomerulus sclerosis, tubular protein casts, focal tubular atrophy, inflammatory cells infiltration and interstitial fibrosis. FN mRNA, PAI-1 mRNA and TGF-P-1 mRNA expressed in renal cortex of 24 months old rats have been much up-regulated. Therapies for each group3decreased urine protein obviously, with no effects on blood pressure, heart rate, kidney/body weight ratio, renal function and serum uric acid of aging rats. ECM expansion, glomerulus sclerosis, and tubular interstitial lesion were ameliorated in treatment groups. FN and PAI-1 gene expression in renal cortex were down-regulated markedly. Therapies for each group showed no significant effects on TGF-P-1 mRNA. Although no differences between the effects of fosinopril and valsartan could be detected, the combination treatment showed more effective than any single therapy in amelioration of ECM expansion and tubular interstitial lesion. The concentration of blood plasma rennin, Ang II and aldosterone decreased, whereas tissue Ang II increased with aging. Renal ACE mRNA was up-regulated in aged group. ATiaRmRNA and AT,bRmRNA were down-regulated in the kidneys of aging rats, however, angiotensin and AT2RmRNA were expressed higher in renal tissue of the aged rats comparing to the 3-month old rats. No marked difference was revealed about ATiaRmRNA expressed in isolated glomuruli between young and aged rats, however, ATiaRmRNA expressed in renal tubules was down-regulated while being up-regulated in renal arteries. ATibRmRNA was down-regulated both in the renal glomurulus and tubules, while being up-regulated in arteries. AT2RmRNA expression was up-regulated obviously in renal tubules, with no changes in glomuruli and tubules. Fosinopril had no significant effect on plasma ACE activity, however, it could decrease ACE mRNA expression in renal tissue, valsartan could increase Ang II consentration in renal tissue. Both the treatment had no significant effects on the concentration of plasma renin or alderstorone, nor did the combination treatment. Fosinopril showed no effect on AT]aR mRNA, ATjbR mRNA, or AT2R mRNA, however, valsartan coul...