Sitagliptin and shock wave-supported peripheral blood derived endothelial progenitor cell therapy effectively preserves residual renal function in chronic kidney disease in rat—role of dipeptidyl peptidase 4 inhibition - 16/02/19

Doi : 10.1016/j.biopha.2019.01.025

Pei-Hsun Sung ^a,^b, Kuan-Hung Chen ^b,^c, Yi-Chen Li ^a, John Y. Chiang ^d,^e, Mel S. Lee ^f,^⁎ , Hon-Kan Yip ^a,^b,^g,^h,^i,^⁎
^a Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan, ROC
^b Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan, ROC
^c Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan, ROC
^d Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan, ROC;
^e Quanzhou University of Information Engineering, Quanzhou, China
^f Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan, ROC
^g Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan, ROC
^h Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan, ROC
ⁱ Department of Nursing, Asia University, Taichung, 41354, Taiwan, ROC

^⁎Corresponding author at: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan, ROC.Division of CardiologyDepartment of Internal MedicineKaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiung83301Taiwan, ROC^⁎⁎Corresponding author.

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Abstract

This study tested whether sitagliptin and shock wave (SW)-assisted circulatory-derived autologous endothelial progenitor cell (EPC) therapy would effectively preserve residual renal function in chronic kidney disease (CKD) induced by 5/6 left-nephrectomy/remove right kidney plus daily feeding high-protein diet (H^PD) in rat. Adult-male SD rats (n = 40) were categorized into group 1 (sham-operated control with H^PD), group 2 (H^PD-CKD), group 3 [H^PD-CKD + EPC (1.2 × 10⁶ cell)/intra-vessel administration by day 14 after CKD-induction], group 4 [H^PD-CKD + SW (0.12 mJ/mm²/180 shorts) at days 14/21/28 after CKD-induction by ultrasound-guided application] and group 5 [H^PD-CKD + SW + EPC + sitagliptin (Sita; 600 mg/kg/day since day 14 after CKD induction)]. All animals were euthanized by day 60. By day 60, renal blood flow (RBF) was highest in group 1 and progressively increased from groups 2 to 5, whereas the levels of creatinine/BUN/proteinuria exhibited an opposite pattern of RBF among the five groups (all p < 0.001). The circulating levels of GLP-1/SDF-1α and protein levels of angiogenesis (VEGF/SDF-1α/CXCR4) and GLP-1R in kidney were progressively increased from groups 1 to 5, whereas circulating DPP4 activity exhibited an opposite pattern of SDF-1α among the groups (all p < 0.0001). The protein expressions of oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptosis (Bax/caspase-3/PARP), fibrosis (Smad3/TGF-ß) and inflammation (TNF-α/NF-κB/MMP-2) and kidney injury score displayed an opposite pattern, whereas the protein expressions of TMP2, endothelial-cell markers (CD31/eNOS) and podocyte integrity biomarkers (podocin/ZO-1/synaptopodin) exhibited an identical pattern of RBF among the groups (all p < 0.001). In conclusion Sita associated SW-assisted EPC effectively protected residual renal function in CKD.

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Keywords : Chronic kidney disease, High-protein diet, Shock wave, Sitagliptin, Endothelial progenitor cells

Plan

Introduction

Materials and methods

Ethics

Rationale of high-protein diet for all CKD animals

Animal model of CKD and animal grouping

Collection of peripheral blood for culturing EPCs

EPCs administered in CKD animals

Procedure and protocol of SW application to rat kidney

Assessment of BUN and creatinine levels

Collection of 24-hr urine for the ratio of urine protein to creatinine at baseline and at days 14 and 60 after CKD Induction

Abdominal ultrasonography for determining renal blood flow

Flow cytometric quantification of EPCs

Biomarkers were assessed using laboratory standard methods and commercial kits

Histopathology scoring of kidney injury at day 60 after CKD induction

Western blot analysis of left kidney specimens

Immunohistochemical and immunofluorescent studies

Statistical analysis

Results

Time courses of BUN, creatinine and ratio of urine protein to creatinine ()

Circulating levels of biomarkers ()

Circulating and bone-marrow levels of EPCs among five groups of animals ()

Time course assessment of renal ultrasonography of renal blood flow and kidney injury score by day 60 after CKD induction ()

Histopathological findings and protein expressions of fibrotic and apoptotic biomarkers by day 60 after CKD induction ()

Endothelial and cellular angiogenesis biomarkers by day 60 after CKD induction (, )

Cellular expressions of podocyte components in kidney parenchyma by day 60 after CKD induction (, )

Cellular expression of Wilm’s tumor suppressor gene 1 (WT-1) and KIM-1 by day 60 after CKD induction ()

Protein expressions of oxidative stress and inflammatory biomarkers by day 60 after CKD induction (supplementary Fig. 1)

Protein expressions of endothelial and angiogenesis biomarkers in kidney parenchyma by day 60 after CKD induction (supplementary Fig. 2)

Initial and final body weight of the animals in five groups

Discussion

Study limitation

Author contributions

Conflicts of interest

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Vol 111

P. 1088-1102 - mars 2019 Retour au numéro

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Sitagliptin and shock wave-supported peripheral blood derived endothelial progenitor cell therapy effectively preserves residual renal function in chronic kidney disease in rat—role of dipeptidyl peptidase 4 inhibition - 16/02/19

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