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.

Kyoko Nitta,Munehiro Kitada,Masakazu Haneda,Keizo Kanasaki,Megumi Kanasaki,Takako Nagai,Daisuke Koya,Sen Shi,Swayam Prakash Srivastava

doi:10.1155/2016/9172157

Kyoko Nitta, Munehiro Kitada + Show 7 more

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https://doi.org/10.1155/2016/9172157

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Abstract

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.

Highlights

Diabetic nephropathy is the most common cause of kidney disease and causes significant health problems [1, 2]
We tried to investigate whether oral administration of antifibrotic peptide AcSDKP can be absorbed from the gastrointestinal tract and increase the plasma levels
We utilized the normal 8-week CD-1 mouse in this experiment and confirmed that, at 2 hours after the oral administration of AcSDKP (1 mg or 10 mg), we found a dose-dependent increase in the levels of AcSDKP in the plasma (Figure 1(a))

Summary

Introduction

Diabetic nephropathy is the most common cause of kidney disease and causes significant health problems [1, 2]. 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 and may display significant differences in organ protection from diabetesassociated damage [7,8,9,10,11]. A recent meta-analysis revealed that ACE-I exhibited stronger organ protection compared to ARB in patients with type 2 diabetes with nephropathy [9, 11] These reports suggested that the biology of ACE in kidney fibrosis is not limited to “angiotensin-conversion” but may involve some angiotensin-independent effects

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