N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Ameliorates the Progression of Renal Dysfunction and Fibrosis in WKY Rats with Established Anti–Glomerular Basement Membrane Nephritis

Omata, M; Taniguchi, Hajime; Koya, Daisuke; Kanasaki, Keizo; Sho, Rumiko; Kato, Yoshimi; Kojima, Ryoji; Haneda, Masakazu; Inomata, Norio

doi:10.1681/asn.2005040385

Cited by 53 publications

(60 citation statements)

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“…36 It was reported recently that Ac-SDKP ameliorated the progression of renal dysfunction and fibrosis in rats with established antiglomerular basement membrane nephritis by reducing macrophage accumulation in the glomeruli and tubulointerstitium. 13 Here we confirmed these findings and demonstrated that Ac-SDKP participates in the anti-inflammatory effect of ACEi in the heart and kidney, because it was partially blocked by the mAb.…”

Section: Discussionsupporting

confidence: 85%

“…9 It also prevented left ventricular (LV) and renal fibrosis in hypertensive rats, 10,11 as well as renal insufficiency and fibrosis in diabetic db/db mice or rats with established antiglomerular basement membrane nephritis. 12,13 The antifibrotic effects of ACEi might be mediated by preventing degradation of endogenous Ac-SDKP and thereby increasing Ac-SDKP in plasma and tissue. 6,14,15 ALDO-salt-induced hypertension is characterized by severe fibrosis in the heart and kidney, as well as extensive inflammatory reactions that are central to stimulation of collagen synthesis.…”

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confidence: 99%

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Role of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline in the Antifibrotic and Anti-Inflammatory Effects of the Angiotensin-Converting Enzyme Inhibitor Captopril in Hypertension

et al. 2007

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Abstract-Angiotensin-converting enzyme inhibitors (ACEis) are known to have antifibrotic effects on the heart and kidney in both animal models and humans. N-acetyl-seryl-aspartyl-lysyl-proline is a natural inhibitor of proliferation of hematopoietic stem cells and a natural substrate of ACEi that was reported to prevent cardiac and renal fibrosis in vivo. However, it is not clear whether N-acetyl-seryl-aspartyl-lysyl-proline participates in the antifibrotic effects of ACEi. To clarify this issue, we used a model of aldosterone-salt-induced hypertension in rats treated with the ACEi captopril either alone or combined with an anti-N-acetyl-seryl-aspartyl-lysyl-proline monoclonal antibody. These hypertensive rats had the following: (1) left ventricular and renal hypertrophy, as well as increased collagen deposition in the left ventricular and the kidney; (2) glomerular matrix expansion; and (3) increased ED1-positive cells and enhanced phosphorylated-p42/44 mitogen-activated protein kinase in the left ventricle and kidney. The ACEi alone significantly lowered systolic blood pressure (Pϭ0.008) with no effect on organ hypertrophy; it significantly lowered left ventricular collagen content, and this effect was blocked by the monoclonal antibody as confirmed by the histological data. As expected, the ACEi significantly decreased renal collagen deposition and glomerular matrix expansion, and these effects were attenuated by the monoclonal antibody. Likewise, the ACEi significantly decreased ED1-positive cells and inhibited p42/44 mitogen-activated protein kinase phosphorylation in the left ventricle and kidney, and these effects were blocked by the monoclonal antibody. We concluded that in aldosterone-salt-induced hypertension, the antifibrotic effect of ACEi on the heart and kidney, is partially mediated by N-acetyl-seryl-aspartyl-lysyl-proline, resulting in decreased inflammatory cell infiltration and p42/44 mitogen-activated protein kinase activation. Key Words: aldosterone-salt Ⅲ hypertension Ⅲ angiotensin-converting enzyme inhibitor Ⅲ Ac-SDKP Ⅲ collagen Ⅲ mitogen-activated protein kinase Ⅲ macrophage/monocyte infiltration A ngiotensin (Ang)-converting enzyme (ACE) inhibitors (ACEis) are important agents for treatment of hypertension, heart failure, and other cardiovascular and renal diseases. In vivo studies showed that ACEi significantly attenuated cardiac fibrosis in rats with heart failure induced by myocardial infarction, 1 spontaneously hypertensive rats, 2 and rats with aldosterone (ALDO)-salt hypertension 3 and also prevented both cardiac and renal fibrosis in mice given deoxycorticosterone acetate-salt. 4 N-acetyl-seryl-aspartyllysyl-proline (Ac-SDKP), a natural inhibitor of hematopoietic stem cell proliferation and a natural substrate of ACEi, 5,6 was reported to inhibit rat cardiac fibroblast proliferation and collagen synthesis 7,8 and mesangial cell proliferation. 9 It also prevented left ventricular (LV) and renal fibrosis in hypertensive rats, 10,11 as well as renal insufficiency and fibrosis in diabe...

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Section: Discussionsupporting

confidence: 85%

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confidence: 99%

Role of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline in the Antifibrotic and Anti-Inflammatory Effects of the Angiotensin-Converting Enzyme Inhibitor Captopril in Hypertension

et al. 2007

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“…Smad7 has been shown to be downregulated in some kidney disease models (49,50), and its overexpression ameliorates renal fibrosis in rat models of ureteral obstruction (51,52) or in a remnant kidney model (53). Conversely, upregulation of Smad7 in podocytes has been observed in some human kidney diseases (54).…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy with an Angiotensin-Converting Enzyme Inhibitor and a Vitamin D Analog Suppresses the Progression of Renal Insufficiency in Uremic Rats

Mizobuchi¹,

Morrissey²,

Finch³

et al. 2007

Journal of the American Society of Nephrology

183

148

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Monotherapy with angiotensin-converting enzyme inhibitors has been shown to be beneficial in suppressing the progression of experimentally induced kidney diseases. Whether such therapy provides additional benefits when combined with vitamin D or an analog of vitamin D has not been established. Rats were made uremic by 5/6 nephrectomy and treated as follows: Uremic ؉ vehicle (UC), uremic ؉ enalapril (30 mg/L in drinking water; E), uremic ؉ paricalcitol (19-nor; 0.8 g/kg, three times a week), and uremic ؉ enalapril ؉ paricalcitol (E ؉ 19-nor). A group of normal rats served as control (NC). BP was significantly elevated in the UC and 19-nor groups compared with the NC group but was indistinguishable from normal in the E and E ؉ 19-nor groups. The decrease in creatinine clearance and the increase in the excretion of urinary protein that were observed in the UC group were ameliorated by the use of E alone or by E ؉ 19-nor (P < 0.05 versus UC). The glomerulosclerotic index was significantly decreased in both the 19-nor (P < 0.01) and E ؉ 19-nor groups (P < 0.01) compared with the UC group. Tubulointerstitial volume was significantly decreased in both the E (P < 0.05) and E ؉ 19-nor groups (P < 0.01) compared with the UC group. Both macrophage infiltration (ED-1-positive cells) and production of the chemokine monocyte chemoattractant protein-1 were significantly blunted in E ؉ 19-nor compared with E group. TGF-␤1 mRNA and protein expression were increased in the UC group (mRNA: 23.7-fold; protein: 29.1-fold versus NC). These increases were significantly blunted in the 19-nor group (mRNA: 7.1-fold; protein: 8.0-fold versus NC) and virtually normalized in the E ؉ 19-nor group (protein: 0.8-fold versus NC). Phosphorylation of Smad2 was also elevated in the UC group (7.6-fold versus NC) but less so in the 19-nor-treated rats (5.5-fold versus NC). When rats were treated with E ؉ 19-nor, the phosphorylation of Smad2 was normal (1.1-fold versus NC). Thus, 19-nor can suppress the progression of renal insufficiency via mediation of the TGF-␤ signaling pathway, and this effect is amplified when BP is controlled via renin-angiotensin system blockade.

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“…140 The smad7 level increases in vivo following AcSDKP administration, supporting the smad7 mediated anti-TGF-b effects of AcSDKP. 141,142 Given that AcSDKP is increased by the inhibition of ACE, AcSDKP might have an important role in the renoprotective effects of ACE-I. 100 This evidence also suggests that the potential anti-TGF-b effects of AcSDKP by I-smad may provide a new therapeutic candidate for progressive kidney fibrosis.…”

Section: Perspective: Anti-fibrosis Therapymentioning

confidence: 99%

Pathophysiology of the aging kidney and therapeutic interventions

2012

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Kidneys are among the organs affected by the aging process. Aging kidneys are characterized by progressive scarring and measurable declines in renal function. Deficiencies in renal function are associated with mortality in all populations. Therefore, if the kidneys age at an accelerated rate relative to the other organs in a particular individual, then slowing or reversing the kidney aging process may be a therapeutically useful strategy. In this review, we will discuss the physiology and pathogenesis of kidney aging and analyze potential therapeutic strategies for halting the aging process in the kidneys.

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N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Ameliorates the Progression of Renal Dysfunction and Fibrosis in WKY Rats with Established Anti–Glomerular Basement Membrane Nephritis

Cited by 53 publications

References 34 publications

Role of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline in the Antifibrotic and Anti-Inflammatory Effects of the Angiotensin-Converting Enzyme Inhibitor Captopril in Hypertension

Role of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline in the Antifibrotic and Anti-Inflammatory Effects of the Angiotensin-Converting Enzyme Inhibitor Captopril in Hypertension

Combination Therapy with an Angiotensin-Converting Enzyme Inhibitor and a Vitamin D Analog Suppresses the Progression of Renal Insufficiency in Uremic Rats

Pathophysiology of the aging kidney and therapeutic interventions

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