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Abstract

Studies in humans have shown that pancreatic transplantation not only arrests but can reverse diabetic nephropathy (NEJM '98). Experimentally studies have suggested that in chronic renal failure due to either renal ablation (5/6 Nx) or toxic nephropathy due to puromycin, interruption of the renin angiotensin system (RAS) may not only arrest progression but may in fact reverse glomerular injury (KI '91, '94). Dahl salt sensitive (DS) rats fed high dietary salt develop hypertension and severe renal injury. We designed a 12 week study to evaluate whether the treatment with an angiotensin receptor-1 (AT1-R) blocker {Candesartan (Cande) given by gavage 10 mg/kg/day} may reverse glomerular injury. DS rats were fed 4% NaCl for 6 weeks and then divided into 3 groups: 1- (HS) was sacrificed, 2- (HS/LS) switched to Low salt (0.5% NaCl), 3- (HS/LS+Cande) switched to 0.5% NaCl and treated with Cande. A 4th group was kept on 0.5% NaCl for the duration of the study. Systolic blood pressure (SBP), 24-hr urinary protein excretion (U-Pr) and kidney weight (KW) were measured. Glomerular injury (GIS) was scored semi-quantitatively to assess the severity and the distribution of lesions as previously described (KI '84). Results: (See Table)

GroupsTime of sacrifice (Weeks)SBP (mmHg)KW (g)U-Pr (mg/24hrs)GIS
HS (n=6)6223±131.7±0.06130±2587±14
HS/LS (n=6)12202±31.7±0.07φ104±14 #,φ50±8φ,#,δ
HS/LS+Cande (n=6)12143±6*1.5±0.05*35±10*20±3*
LS (n=6)12154±2*1.4±0.03*53±2*10±7*
GroupsTime of sacrifice (Weeks)SBP (mmHg)KW (g)U-Pr (mg/24hrs)GIS
HS (n=6)6223±131.7±0.06130±2587±14
HS/LS (n=6)12202±31.7±0.07φ104±14 #,φ50±8φ,#,δ
HS/LS+Cande (n=6)12143±6*1.5±0.05*35±10*20±3*
LS (n=6)12154±2*1.4±0.03*53±2*10±7*

(p < 0.05

*

* in comparison to HS

φ

to LS

#

to HS/LS+Cande

δ

to HS)

GroupsTime of sacrifice (Weeks)SBP (mmHg)KW (g)U-Pr (mg/24hrs)GIS
HS (n=6)6223±131.7±0.06130±2587±14
HS/LS (n=6)12202±31.7±0.07φ104±14 #,φ50±8φ,#,δ
HS/LS+Cande (n=6)12143±6*1.5±0.05*35±10*20±3*
LS (n=6)12154±2*1.4±0.03*53±2*10±7*
GroupsTime of sacrifice (Weeks)SBP (mmHg)KW (g)U-Pr (mg/24hrs)GIS
HS (n=6)6223±131.7±0.06130±2587±14
HS/LS (n=6)12202±31.7±0.07φ104±14 #,φ50±8φ,#,δ
HS/LS+Cande (n=6)12143±6*1.5±0.05*35±10*20±3*
LS (n=6)12154±2*1.4±0.03*53±2*10±7*

(p < 0.05

*

* in comparison to HS

φ

to LS

#

to HS/LS+Cande

δ

to HS)

Thus, reduction of dietary salt (HS/LS) did not significantly reduce SBP or U-Pr, although it modestly reduced GIS. On the other hand, AT1-R blockade (HS/LS+Cande) normalized SBP, U-Pr, and not only arrested, but reversed glomerular injury. Clinically, longitudinal studies with serial renal biopsies should reveal a) whether AT1-R blockade can reverse glomerular injury and b) whether doses beyond those necessary for blood pressure control are required for this effect.

Glomerular injury, renin angiotensin system, AT1- receptor blocker
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© American Journal of Hypertension, Ltd. 2001
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