Increased gene expression of components of the renin-angiotensin system inglomeruli of genetically hypertensive rats

Objective The renin-angiotensin system (RAS) is implicated in the developme nt of hypertensive glomerulosclerosis, However, no experimental evidence ex ists that clearly demonstrates activation of glomerular RAS in hypertensive nephropathy, We used stroke-prone spontaneously hypertensive rats (SHRSP) to examine whether RAS components are increased in glomeruli of SHRSP and w hether this increase leads to an increase in mRNA levels for transforming g rowth factor-beta 1 (TGF-beta 1), Methods We examined the sequential changes of urinary albumin excretion (UA E), morphology, and glomerular mRNA expression for TGF-beta 1 and fibronect in (FN) in relation to glomerular mRNA expression for angiotensinogen (ATN) , angiotensin converting enzyme (ACE), angiotensin II type 1a (AT1a), and t ype 1b (AT1b) receptors, and intervention with angiotensin II type 1. recep tor antagonist candesartan and equihypotensive hydralazine, Results In SHRSP, UAE was normal at 9 weeks of age, but became higher, begi nning at 12 weeks of age, than that in the age-matched Wistar-Kyoto (WKY) r ats, while SH RSP showed no glomerulosclerosis until 14 weeks of age; it wa s marked at 24 weeks. Plasma renin activity and plasma angiotensin II level was equivalent in the 9- and 12-week-old SHRSP and the WKY rats; both para meters, however, were elevated in 24-week-old SHRSP as compared with age-ma tched control. RNase protection assays showed that glomerular levels of ATN , ACE, and AT1a and AT1b receptors mRNA were significantly increased in 9-, 12-, and 14-week-old, but not in 24-week-old SHRSP, compared with age-matc hed WKY rats. Northern blot analysis showed that glomerular levels of TGF-b eta 1 and FN mRNA were higher in SHRSP than in WKY rats at all time points. Candesartan reduced UAE to control levels, whereas hydralazine reduced UAE but not to control levels. Candesartan administration for 12 weeks virtual ly prevented the progression of glomerulosclerosis. While candesartan reduc ed mRNA levels for RAS components, TGF-beta 1 and FN to control levels, hyd ralazine was not effective in this respect. Conclusion Results suggest that increases in glomerular RAS components that occur independently of circulating RAS alter glomerular permselectivity an d increase the glomerular expression of TGF-PI and FN in young SHRSP. Findi ngs in old SHRSP suggest that altered glomerular permselectivity and an inc reased glomerular expression of TGF-beta 1 and FN may be associated with th e activation of systemic RAS, JHypertens 2000, 18:1247-1255 (C) Lippincott Williams & Wilkins.