The biological significance of angiotensin-converting enzyme inhibition to combat kidney fibrosis

Nagai, Takako; Nitta, Kyoko; Kanasaki, Megumi; Koya, Daisuke; Kanasaki, Keizo

doi:10.1007/s10157-014-1000-3

Cited by 13 publications

(8 citation statements)

References 105 publications

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“…Among RAS inhibitors, angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB) are two major drug classes prescribed to delay diabetic nephropathy progression [ 6 , 7 ]. These two drug classes may exhibit similar renoprotective effects but also may display significant differences in organ protection from diabetes-associated damage [ 7 – 11 ]. It is well known that the maximum dose of ACE-I, which abolishes circulatory angiotensin II, cannot inhibit local angiotensin II production in renal tubules [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…There are two catalytic domains, N-terminal and C-terminal, in the ACE [ 7 ]. Angiotensin I is mainly metabolized into angiotensin II at the C-terminal catalytic site of ACE; the N-terminal specific substrate N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is the antifibrotic peptide [ 15 ] synthesized through protein processing, which is generated by prolyl oligopeptidase from the precursor peptide thymosin β 4 [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Oral Administration of N-Acetyl-seryl-aspartyl-lysyl-proline Ameliorates Kidney Disease in Both Type 1 and Type 2 Diabetic Mice via a Therapeutic Regimen

Nitta

Shu

Nagai

et al. 2016

BioMed Research International

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Kidney fibrosis is the final common pathway of progressive kidney diseases including diabetic nephropathy. Here, we report that the endogenous antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), the substrate of angiotensin-converting enzyme (ACE), is an orally available peptide drug used to cure kidney fibrosis in diabetic mice. We utilized two mouse models of diabetic nephropathy, streptozotocin- (STZ-) induced type 1 diabetic CD-1 mice and type 2 diabetic nephropathy model db/db mice. Intervention with the ACE inhibitor imidapril, oral AcSDKP, or imidapril + oral AcSDKP combination therapy increased urine AcSDKP levels. AcSDKP levels were significantly higher in the combination group compared to those of the other groups. AcSDKP oral administration, either AcSDKP alone or in addition to imidapril, ameliorated glomerulosclerosis and tubulointerstitial fibrosis. Plasma cystatin C levels were higher in both models, at euthanasia, and were restored by all the treatment groups. The levels of antifibrotic miRs, such as miR-29 or let-7, were suppressed in the kidneys of both models; all treatments, especially the combination of imidapril + oral AcSDKP, restored the antifibrotic miR levels to a normal value or even higher. AcSDKP may be an oral antifibrotic peptide drug that would be relevant to combating fibroproliferative kidney diseases such as diabetic nephropathy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oral Administration of N-Acetyl-seryl-aspartyl-lysyl-proline Ameliorates Kidney Disease in Both Type 1 and Type 2 Diabetic Mice via a Therapeutic Regimen

Nitta

Shu

Nagai

et al. 2016

BioMed Research International

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“…It is unclear whether the increase of circulating Ac-SDKP mediates some of the beneficial effects of ACE inhibitor treatment in CKD. 54 A study investigating the role of endogenous Ac-SDKP in fibrosis demonstrated that downregulation of Ac-SDKP in rats by administrating a POP inhibitor (S17092, 40 mg/kg/day) increased collagen deposition and promoted cardiac and renal perivascular fibrosis and glomerulosclerosis. 55 These findings suggested that exogenous Ac-SDKP could have an antifibrotic effect.…”

Section: The Therapeutic Potential Of Thymosin-b4 and Its Derivativesmentioning

confidence: 99%

Thymosin-β4: A key modifier of renal disease

Vasilopoulou

Riley

Long³

2018

Expert Opinion on Biological Therapy

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There is an urgent need for new treatments for chronic kidney disease (CKD). Thymosin-β4 is a peptide that reduces inflammation and fibrosis and has the potential to restore endothelial and epithelial cell injury, biological processes involved in the pathophysiology of CKD. Therefore, thymosin-β4 could be a novel therapeutic direction for CKD. Areas covered: Here, we review the current evidence on the actions of thymosin-β4 in the kidney in health and disease. Using transgenic mice, two recent studies have demonstrated that endogenous thymosin-β4 is dispensable for healthy kidneys. In contrast, lack of endogenous thymosin-β4 exacerbates mouse models of glomerular disease and angiotensin-II-induced renal injury. Administration of exogenous thymosin-β4, or its metabolite, Ac-SDKP, has shown therapeutic benefits in a range of experimental models of kidney disease. Expert opinion: The studies conducted so far reveal a protective role for thymosin-β4 in the kidney and have shown promising results for the therapeutic potential of exogenous thymosin-β4 in CKD. Further studies should explore the mechanisms by which thymosin-β4 modulates kidney function in different types of CKD. Ac-SDKP treatment has beneficial effects in many experimental models of kidney disease, thus supporting its potential use as a new treatment strategy.

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“…Even with the use of such renin-angiotensin system inhibitors, we still have no clear answer as to whether angiotensinconverting enzyme inhibitors and angiotensin receptor blockers have the same effects. 8 However, there is still some hope to combat diabetes. Recently, both preclinical and clinical studies have demonstrated some potential for incretin-based therapies to combat kidney diseases in diabetic patients.…”

Section: Acknowledgmentsmentioning

confidence: 99%