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

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.

SIRT3 deficiency leads to induction of abnormal glycolysis in diabetic kidney with fibrosis

“…Authors confirm that all the experiments are performed in accordance to Japanese guidelines and regulations for scientific and ethical experimentation. The induction of diabetes in the CD-1 and C57Bl6 KsJ mice was performed according to the previously established experimental protocol 32 – 34 , 58 , 59 . In brief, 8-week-old CD-1 and C57Bl6KsJ mice were induced diabetes with the single intraperitoneal injection of streptozotocin (STZ) at 200 mg/kg in 10 mmol/l citrate buffer (pH 4.5).…”

Inhibition of Angiotensin-Converting Enzyme Ameliorates Renal Fibrosis by Mitigating DPP-4 Level and Restoring Antifibrotic MicroRNAs

“…ACEi treatment increases the plasma level of AcSDKP by fivefold [16]. Earlier researches in support of antifibrotic activity of AcSDKP includes the inhibition of TGF-β-induced expression of plasminogen activator inhibitor-1 and α2 collagen in human mesangial cells by inhibiting the smad 2/3 signaling pathway [17]; Shibuya et al reported that AcSDKP prevented renal insufficiency and mesangial matrix expansion in diabetic db/db mice [18]; AcSDKP showed protective effects in various experimental animal models [19,20]. We here aimed to explore the ACEi and ARB actions on elevated DPP-4 level in regulating kidney fibrosis and to unravel the intermediary mechanisms involved.…”

The Absence of the ACE N-Domain Decreases Renal Inflammation and Facilitates Sodium Excretion during Diabetic Kidney Disease

“…23,25 Several studies have demonstrated that chronic administration of AcSDKP prevents kidney fibrosis and improves renal insufficiency in rodent models of diabetes. [26][27][28][29] Indeed, a recent study shows that mice lacking thymosin b4 have lower levels of renal AcSDKP and show an exacerbated kidney injury in response to angiotensin II infusion. 30 However, whether this tetrapeptide has a role in the abnormal sodium handling observed during diabetic nephropathy is unknown.…”