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Saxagliptin attenuates glomerular podocyte injury by increasing the expression of renal nephrin and podocin in type 2 diabetic rats

  • Yuanyuan Hu
  • Shandong YeEmail author
  • Yan Xing
  • Lijuan Lv
  • Wen Hu
  • Wan Zhou
Original Article
  • 126 Downloads
Part of the following topical collections:
  1. Diabetic Nephropathy

Abstract

Aims

To observe the effects of saxagliptin on the expression of mitogen-activated protein kinase 38 (p38MAPK), nephrin and podocin in renal tissue in type 2 diabetic (T2DM) rats, and to explore the possible mechanism of its renal protection.

Methods

Forty-eight male Sprague–Dawley rats were used for the study and divided into four different groups: normal controls (Group NC), DM controls (Group DM), DM + glibenclamide (Group Su) and DM + saxagliptin (Group Sa). The day drug administration started was defined as week 0. After 12 weeks, hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG), urea nitrogen (BUN) and creatinine (Cr) in serum were detected, simultaneously albumin and creatinine in urine were measured, respectively, and then urinary albumin/creatinine ratio (UACR) was calculated. The pathological morphology of kidney tissue in different groups was observed, and the expression of nephrin and podocin mRNA and protein in kidney tissue were detected.

Results

(1) After 12 weeks, FBG and HbA1c in Group Su and Group Sa were significantly lower than those in Group DM (both P < 0.05), while there was no significant difference between Group Su and Group Sa. TC, TG and UACR in Group Sa were significantly decreased than those in Group DM. (2) When compared with Group DM, the kidney weight/body weight ratios, the average width of glomerular basement membrane and foot process fusion ratio were all improved in Group Sa after 12 weeks. (3) The expression of p38MAPK mRNA and protein was significantly decreased, while nephrin and podocin mRNA and protein were significantly higher in Group Sa than those in Group DM after 12 weeks. (4) A significant negative correlation was detected between p38MAPK mRNA and nephrin (r = − 0.421, P = 0.009) and podocin mRNA (r = − 0.570, P = 0.000), respectively.

Conclusions

Saxagliptin can reduce urinary albumin excretion and exert renal protective effect, especially on podocytes in T2DM rats. The mechanism may be related to its inhibition of renal p38MAPK signaling pathway and the increase in the expression of nephrin and podocin in renal tissue, which is independent of its hypoglycemic effect.

Keywords

Diabetes mellitus Saxagliptin DPP-4 Nephrin Podocin p38MAPK 

Notes

Acknowledgements

This study was supported by the National Natural Science Foundation of China (81800731) and Local Scientific and Technological Development Project guided by Central Government of China (No: 2017070802D147).

compliance with ethical standards

Conflict of interest

All the authors declare that they have no conflict of interest.

Ethical approval

The study protocol was approved by the Ethics Committee of Anhui provincial hospital, Medical Institution Animal Care and Research Advisory Committee (Hefei, China).

References

  1. 1.
    Fechete R, Heinzel A, Perco P et al (2011) Mapping of molecular pathways, biomarkers and drug targets for diabetic nephropathy. Proteomics Clin Appl 5:354–366CrossRefPubMedGoogle Scholar
  2. 2.
    Morita M, Uchigata Y, Hanai K et al (2011) Association of urinary type IV collagen with GFR decline in young patients with type 1 diabetes. Am J Kidney Dis 58:915–920CrossRefPubMedGoogle Scholar
  3. 3.
    Siu B, Saha J, Smoyer WE et al (2006) Reduction in podocyte density as a pathologic feature in early diabetic nephropathy in rodents: prevention by lipoic acid treatment. BMC Nephrol 15:6CrossRefGoogle Scholar
  4. 4.
    Lian H, Cheng Y, Wu X (2017) TMEM16A exacerbates renal injury by activating P38/JNK signaling pathway to promote podocyte apoptosis in diabetic nephropathy mice. Biochem Biophys Res Commun 487:201–208CrossRefPubMedGoogle Scholar
  5. 5.
    Komers R, Lindsley JN, Oyama TT et al (2007) Renal p38 MAP kinase activity in experimental diabetes. Lab Invest 87:548–558CrossRefPubMedGoogle Scholar
  6. 6.
    Adhikary L, Chow F, Nikolic-Paterson DJ et al (2004) Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy. Diabetologia 47:1210–1222CrossRefPubMedGoogle Scholar
  7. 7.
    Gonçalves GL, Costa-Pessoa JM, Thieme K et al (2018) Intracellular albumin overload elicits endoplasmic reticulum stress and PKC-delta/p38 MAPK pathway activation to induce podocyte apoptosis. Sci Rep 8:18012CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Duvnjak L, Perković MN, Blaslov K (2017) Dipeptidyl peptidase-4 activity is associated with urine albumin excretion in type 1 diabetes. J Diabetes Complications 31:218–222CrossRefPubMedGoogle Scholar
  9. 9.
    Mosenzon O, Leibowitz G, Bhatt DL et al (2017) Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial. Diabetes Care 40:69–76CrossRefPubMedGoogle Scholar
  10. 10.
    Herman-Edelstein M, Thomas MC, Thallas-Bonke V et al (2011) Dedifferentiation of immortalized human podocytes in response to transforming growth factor-β: a model for diabetic podocytopathy. Diabetes 60:1779–1788CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ziyadeh FN, Wolf G (2008) Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabet Rev 4:39–45CrossRefGoogle Scholar
  12. 12.
    Welsh GI, Saleem MA (2010) Nephrin-signature molecule of the glomerular podocyte? J Pathol 220:328–337PubMedGoogle Scholar
  13. 13.
    Denhez B, Geraldes P (2017) Regulation of Nephrin Phosphorylation in Diabetes and Chronic Kidney Injury. Adv Exp Med Biol 966:149–161CrossRefPubMedGoogle Scholar
  14. 14.
    Li X, Gao Z, Gao H et al (2017) Nephrin loss is reduced by grape seed proanthocyanidins in the experimental diabetic nephropathy rat model. Mol Med Rep 16:9393–9400CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wadie W, El-Tanbouly DM (2017) Vinpocetine mitigates proteinuria and podocytes injury in a rat model of diabetic nephropathy. Eur J Pharmacol 814:187–195CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2019

Authors and Affiliations

  • Yuanyuan Hu
    • 1
    • 2
  • Shandong Ye
    • 2
    Email author
  • Yan Xing
    • 3
  • Lijuan Lv
    • 2
  • Wen Hu
    • 4
  • Wan Zhou
    • 2
  1. 1.School of MedicineShandong UniversityShandongChina
  2. 2.Department of Endocrinology, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and MedicineUniversity of Science and Technology of ChinaHefeiChina
  3. 3.Endocrinological Laboratory of Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and MedicineUniversity of Science and Technology of ChinaHefeiChina
  4. 4.Department of Pathology Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and MedicineUniversity of Science and Technology of ChinaHefeiChina

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