Effects of chronic inhibition of ACE and AT₁receptors on glomerular injury in Dahl salt-sensitive rats

Abstract

To elucidate the contribution of the renin-angiontensin system (RAS) to glomerular injury in salt-sensitive hypertension, we investigated the chronic effects of the angiotensin I-converting enzyme inhibitor cilazapril and the angiotensin II type 1-receptor antagonist (AT1a) TCV-116 in Dahl-Iwai rats. Dahl salt-sensitive (S) rats receiving 8% salt diet for 6 wk were simultaneously treated with cilazapril ( n = 6), TCV-116 ( n = 6), or saline ( n = 14). The 8% salt diet markedly increased systolic blood pressure (SBP), urinary protein, and N-acetyl-β-glucosaminidase (NAG) excretion compared with 0.3% salt-treated S ( n = 6) or salt-resistant ( n = 6) rats. Although neither cilazapril nor TCV-116 reduced the elevated SBP, TCV-116 significantly lowered urinary protein and NAG excretion. Histologically, 8% salt treatment in S rats induced progressive sclerotic and proliferative glomerular changes, which were ameliorated by both drugs. TCV-116 increased the glomerular diameter. Immunofluorescence demonstrated the increased level of type III collagen in the mesangium of 8% salt-treated S rats, which was completely reversed by TCV-116. Competitive RT-PCR of mRNA extracted from the glomeruli revealed that 8% salt treatment significantly increased the levels of proliferating cell nuclear antigen (PCNA) and platelet-derived growth factor B-chain and that TCV-116 significantly reduced the levels of PCNA and transforming growth factor-β1 (TGF-β1). Thus, although the chronic RAS-inhibition in salt-sensitive hypertension exerted a histologically renoprotective effect by both ways without lowering blood pressure, the RAS inhibition due to AT1a had more beneficial advantages of reducing proteinuria and attenuating the levels of glomerular TGF-β1 and extracellular matrix.

AT1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: preservation of kidney tissue mass using candesartan

“…The results with ACE inhibition were not surprising, however, as non-ACE-mediated renal production of angiotensin II was likely sustained despite ACE inhibition (18,38). Consistent with this hypothesis, previous data by Otsuka et al (41,42) and Noda et al (39,40) suggested greater renoprotective effects when direct AT 1A inhibition was utilized compared with ACE inhibition in various models of renal injury.…”

Enhancement of Intrarenal Angiotensinogen in Dahl Salt-Sensitive Rats on High Salt Diet

“…However, recent studies suggest that treatment with Ang I-converting enzyme inhibitors or Ang II type I receptor antagonists reduces cardiac and/or renal dysfunction in DS rats made hypertensive by a HS diet. [5][6][7][8][9][10] Furthermore, Nakaya et al 15 reported that prepubertal treatment with an Ang II type I receptor antagonist causes partial attenuation of hypertension and ameliorates the renal damage in adult DS rats fed HS. These data suggest that the local RAS may contribute to development of hypertension and renal dysfunction in this model.…”

“…Although generally considered to be characterized by a low activity of circulating RAS, recent studies indicate that treatment with angiotensin (Ang) I-converting enzyme inhibitors or Ang II type I receptor antagonists reduces cardiac and/or renal dysfunction in DS rat fed a high salt diet (HS). [5][6][7][8][9][10] These findings suggest that the local RAS may be inappropriately activated and contribute to the development of hypertension in this animal model.Previous studies have demonstrated that Ang II infusions to normal rats result in paradoxical increases in renal expression of AGT mRNA 11,12 and protein. 13 Furthermore, urinary excretion of AGT was significantly increased in Ang II-infused rats, which was associated with an enhancement of intrarenal Ang II levels.…”

“…Although generally considered to be characterized by a low activity of circulating RAS, recent studies indicate that treatment with angiotensin (Ang) I-converting enzyme inhibitors or Ang II type I receptor antagonists reduces cardiac and/or renal dysfunction in DS rat fed a high salt diet (HS). [5][6][7][8][9][10] These findings suggest that the local RAS may be inappropriately activated and contribute to the development of hypertension in this animal model.…”

Enhanced expression of bone morphogenetic protein system in aldosterone-treated mouse kidneys

“…Histological examination of glomeruli was microscopically performed as we previously reported. 16 Histologic assessment included measurement of the diameter of each of 200 randomly selected glomeruli in each experimental group. The total number of cells containing nuclei in each glomerulus of at least 100 glomeruli in each specimen was counted.…”