Spironolactone in Combination with Cilazapril Ameliorates Proteinuria and Renal Interstitial Fibrosis in Rats with Anti-Thy-1 Irreversible Nephritis

Asai, Mitsuoki; Monkawa, Toshiaki; Marumo, Takeshi; Fukuda, Seiichi; Tsuji, Mihoko; Yoshino, Mihoko; Kawachi, Hiroshi; Shimizu, Fujio; Hayashi, Matsuhiko; Saruta, Takao

doi:10.1291/hypres.27.971

Cited by 26 publications

(13 citation statements)

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“…Available evidence supports the use of aldosterone antagonists in patients with proteinuria not adequately controlled by ACE inhibitors or ARBs and in patients with chronic kidney disease (CKD) [ 9 ]. Those results have also been observed in experimental animal models with GN [ 10 – 12 ]. The previous findings led us to hypothesize that aldosterone plays a role in the development of glomerular injury and the increased proteinuria seen in patients with GN.…”

Section: Introductionsupporting

confidence: 70%

Efficacy of low-dose spironolactone on top of angiotensin receptor blockade in patients with glomerulonephritis

Lee

Moon

et al. 2018

Kidney Res Clin Pract.

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BackgroundPrevious studies have shown that aldosterone antagonists have a proteinuria-lowering effect in patients with proteinuria and progressive proteinuric disease not adequately controlled by the use of angiotensin receptor blockers (ARBs). Aldosterone antagonists, in combination with ARBs, might improve proteinuria in patients with glomerulonephritis (GN).MethodsIn the present retrospective study, we evaluated the proteinuria-lowering effect and drug safety of low-dose spironolactone (12.5 mg/day) in 42 patients with GN being treated with an ARB.ResultsProteinuria decreased from a mean total-protein-to-creatinine (TP/Cr) ratio of 592.3 ± 42.0 mg/g at baseline to 335.6 ± 43.3 mg/g after three months of treatment with spironolactone (P < 0.001). After the initial three months, the mean TP/Cr ratio increased progressively at six, nine, and 12 months; however, it was still less than the baseline value (P = 0.001, < 0.001, and < 0.001, respectively). Although serum Cr levels increased significantly at three and nine months compared with baseline (P = 0.036 and 0.026, respectively), there was no time effect of treatment (P = 0.071). Serum potassium levels tended to increase with time (P = 0.118), whereas systolic and diastolic blood pressures decreased with time (P = 0.122 and 0.044, respectively).ConclusionLow-dose spironolactone in combination with an ARB reduced proteinuria in patients with GN, which could represent a novel treatment option in individuals whose proteinuria is not optimally controlled by the use of ARBs alone.

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Section: Introductionsupporting

confidence: 70%

Efficacy of low-dose spironolactone on top of angiotensin receptor blockade in patients with glomerulonephritis

Lee

Moon

et al. 2018

Kidney Res Clin Pract.

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“…In another experimental model, Asai et al (29) reported that combination therapy with spironolactone and cilazapril in anti-Thy-1-antibody-induced nephritis in uninephrectomized rats ameliorated proteinuria and renal interstitial fibrosis. These findings suggest that chronic combination therapy may be a potentially useful treatment for hypertensive rats.…”

Section: Fig 7 Comparison Of Aldosterone Infusion In the Absence Anmentioning

confidence: 99%

Cardioprotective Mechanisms of Spironolactone Associated with the Angiotensin-Converting Enzyme/Epidermal Growth Factor Receptor/Extracellular Signal-Regulated Kinases, NAD(P)H Oxidase/Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1, and Rho-Kinase Pathways in Aldosterone/Salt-Induced Hypertensive Rats

et al. 2005

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“…The present data suggest that increased aldosterone due to "aldosterone escape" could be another important contributor to renal fibrosis because aldosterone interacts synergistically with TGF-ß to increase PAI-1 overexpression and subsequently inhibit ECM degradation. If it acts in vivo, this synergistic effect may explain the beneficial effects of combination therapy with an Ang II blocker and an aldosterone blocker that have been observed in patients with heart failure, diabetic nephropathy and nephritic range albuminuria (11,44,46,49) and in animal models with hypertension and glomerulonephritis (2,31,41).…”

Section: Synergistic Effect Of Tgf-1 and Aldosterone On Ecm Degradatimentioning

confidence: 99%

Aldosterone and TGF-β₁synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells

Huang¹,

Xu²,

Kahng³

et al. 2008

American Journal of Physiology-Renal Physiology

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Aldosterone is thought to modulate renal fibrosis, in part, through increasing plasminogen activator inhibitor type 1 (PAI-1), a major inhibitor of ECM degradation. The present study investigated aldosterone effects on PAI-1 and transforming growth factor (TGF)-beta(1) and asked whether PAI-1 effects were TGF-beta mediated and whether aldosterone and TGF-beta(1) acted synergistically to increase PAI-1 and decrease ECM degradation. Rat mesangial cells (MCs) and fibroblast cells [normal rat kidney (NRK)-49F] were used. (3)H-labeled ECM was produced by MCs. The effect of aldosterone and TGF-beta on ECM degradation by newly plated MCs or NRK-49F was measured by the release of (3)H into medium. Aldosterone markedly increased PAI-1 mRNA and protein in both cell types, increases completely blocked by spironolactone and partially blocked by TGF-beta neutralizing antibody. Adding both aldosterone and TGF-beta(1) produced PAI-1 mRNA and protein increases higher than the sum of increases seen with either compound alone. Aldosterone or TGF-beta(1) alone inhibited matrix degradation by 39 and 49% in MCs and 21 and 23% in NRK-49F, respectively. When both compounds were added, matrix degradation was further decreased by 93% in MCs and 61% in NRK-49F. The results indicate that aldosterone-induced PAI-1 increases are partially mediated by TGF-beta(1) and lead to decreased ECM degradation. While aldosterone alone induced TGF-beta(1) weakly, aldosterone and TGF-beta(1) added together produced dramatic synergistic effects on PAI-1 production and subsequent ECM accumulation. Thus the elevated aldosterone induced by renin-angiotensin-aldosterone system activation may amplify renin-angiotensin-aldosterone system profibrotic actions.

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Spironolactone in Combination with Cilazapril Ameliorates Proteinuria and Renal Interstitial Fibrosis in Rats with Anti-Thy-1 Irreversible Nephritis

Abstract: Blockade of the renin-angiotensin system has been established as a treatment for heart failure with hypertension and left ventricular hypertrophy, and for progressive kidney diseases. The present study was con-

Cited by 26 publications

References 25 publications

Efficacy of low-dose spironolactone on top of angiotensin receptor blockade in patients with glomerulonephritis

Efficacy of low-dose spironolactone on top of angiotensin receptor blockade in patients with glomerulonephritis

Aldosterone and TGF-β₁synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells

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Spironolactone in Combination with Cilazapril Ameliorates Proteinuria and Renal Interstitial Fibrosis in Rats with Anti-Thy-1 Irreversible Nephritis

Abstract: Blockade of the renin-angiotensin system has been established as a treatment for heart failure with hypertension and left ventricular hypertrophy, and for progressive kidney diseases. The present study was con-

Cited by 26 publications

References 25 publications

Efficacy of low-dose spironolactone on top of angiotensin receptor blockade in patients with glomerulonephritis

Efficacy of low-dose spironolactone on top of angiotensin receptor blockade in patients with glomerulonephritis

Aldosterone and TGF-β1synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells

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Product

Resources

About

Aldosterone and TGF-β₁synergistically increase PAI-1 and decrease matrix degradation in rat renal mesangial and fibroblast cells