Enhanced Intrarenal Angiotensinogen Contributes to Early Renal Injury in Spontaneously Hypertensive Rats

Abstract

This study was performed to determine whether augmented intrarenal angiotensinogen may contribute to the enhanced renal angiotensin II (Ang II) and associated tissue injury in spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto rats (WKY) were maintained on a normal diet and killed at either 7 or 14 wk of age. Two groups of SHR received either an Ang II type 1 receptor blocker (ARB; olmesartan, 5 mg/d) or a triple therapy (hydralazine 7.5 mg/d, reserpine 0.15 mg/d, and hydrochlorothiazide 3 mg/d [HRH]) during weeks 7 through 14. Systolic BP and renal Ang II were significantly increased in SHR-14 (n ‫؍‬ 8) compared with WKY-7, WKY-14, and SHR-7 (n ‫؍‬ 8 each), and ARB treatment prevented these increases (n ‫؍‬ 8). However, whereas HRH treatment prevented the development of hypertension in SHR, this combination therapy failed to decrease renal Ang II (n ‫؍‬ 8). With the use of urine samples or fixed renal sections, renal injuries in rats were quantified in a semiautomated manner by the following six parameters: (1) urinary excretion rate of total protein, (2) glomerular sclerosis, (3) interstitial expansion, (4) and (5) numbers of monocytes/macrophages in interstitium or glomeruli, and (6) arterial proliferation. Angiotensinogen mRNA and protein levels in kidney cortex, measured by real-time reverse transcriptase-PCR and Western blot analysis, respectively, and all six parameters of renal damage were changed in parallel, and ARB treatment also prevented these increases. However, HRH treatment failed to prevent these increases. These results indicate that SHR have enhanced intrarenal angiotensinogen production that contributes to increased Ang II levels leading to the development of hypertension and renal injury in this strain. S pontaneously hypertensive rats (SHR) have been used as a model of hypertension (1). Mature SHR are reported to have low plasma renin activity (2), which has been interpreted as being indicative of an overall suppression of the renin-angiotensin system (RAS) (3). However, few studies of angiotensinogen have been carried out in these rats. Although generally considered to be characterized by a low activity of circulating RAS, recent studies indicate that treatment with angiotensin I (Ang I)-converting enzyme (ACE) inhibitors and/or Ang II type I (AT1) receptor blocker (ARB) reduces cardiac and/or renal dysfunction in SHR (4 -6). These findings suggest that the intrarenal RAS may be inappropriately activated and in turn contribute to the development of hypertension and hypertension-induced renal damages in this animal model.We recently reported that Dahl-salt sensitive rats on a highsalt diet have an inappropriate augmentation of intrarenal angiotensinogen, which may contribute to impaired sodium excretion and the development of hypertension in this strain (7,8). These results prompted us to perform further experiments to evaluate the intrarenal level of angiotensinogen in other animal models of hypertension. This study was performed to determine whether an augmented intrarenal angiot...

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

“…12,38 Previous reports of activated local RAS with an increased local production of Ang II and an expression of AT1 receptor in experimental rats modeling hypertension, diabetes mellitus and subtotal nephrectomy support this assertion. [41][42][43] Taken together, these results suggest that ARBs exhibit renoprotective effects by blocking local RAS in the kidney.…”

Enhanced intrarenal oxidative stress and angiotensinogen in IgA nephropathy patients

“…Twenty consecutive microscopic fields were examined for each slide and the averaged intensities were obtained for each slide. The measurements were made in an unbiased blended manner without knowledge of source of the tissue as previously described [20][21][22][23][24][25].…”

Involvements of Rho-Kinase and TGF-β Pathways in Aldosterone-Induced Renal Injury

“…The severity of glomerular proliferation, interstitial fibrosis, and tubular proteinaceous cast scores were evaluated using light microscopy according to previously described methods (4,25,(33)(34)(35)(36)(37). Briefly, glomerular proliferative lesions were scored into five grades as follows: 0, no proliferation; 1, minor (segmental lesion Ͻ25%); 2, mild (segmental lesion Ͼ25% but Ͻ50%); 3, moderate (diffuse proliferation without severe sclerotic change); and 4, severe (diffuse proliferation with nearly complete sclerosis) (4,33,34,36). A minimum of 40 glomeruli were examined in each PAS-stained specimen.…”

“…A minimum of 40 glomeruli were examined in each PAS-stained specimen. The severity of tubulointerstitial fibrosis was assessed by counting the percentage of injured areas per field and then scored as follows: 0, normal interstitium; 0.5, Ͻ5% of areas injured; 1, 5 to 15%; 1.5, 16 to 25%; 2, 26 to 35%; 2.5, 36 to 45%; and 3, Ͼ45% (35,36). A minimum of 20 fields were evaluated for each Masson's trichromestained specimen.…”