Vol 72, No 6 (2021)
Original paper
Published online: 2021-10-06

open access

Page views 7169
Article views/downloads 924
Get Citation

Connect on Social Media

Connect on Social Media

PEDF relieves kidney injury in type 2 diabetic nephropathy mice by reducing macrophage infiltration

Li Li1, Lan Zhang1, Danyan Chen1, Keping Yu1, Hua Gan2, Gangyi Yang1
Pubmed: 34647607
Endokrynol Pol 2021;72(6):643-651.


Introduction: Pigment epithelium-derived factor (PEDF) is a multifunctional protein with anti-angiogenic, antioxidant and anti-inflammatory properties. PEDF is involved in the pathogenesis of diabetic retinopathy, but its exact role in diabetic kidneys remains unclear. P78-PEDF is an active peptide sequence consisting of 44 amino acids with biological activity similar to that of PEDF. The present study aimed to investigate whether PEDF can alleviate renal damage in type 2 diabetic nephropathy mice by inhibiting macrophage infiltration.

Material and methods: The db/db mice were randomly divided into a diabetes PEDF intervention group (DM-P78-PEDF), a diabetes empty carrier intervention group (DM-Vehicle), and a diabetes mellitus group (DM). Subsequently, they were injected subcutaneously P78-PEDF (0.3 μg/g/d) and PBS for 6 weeks. The ratio of kidney weight to body weight was observed in the mice. An automatic biochemical analyser was used to determine fasting blood glucose (GLU), blood urea nitrogen (UREA), serum creatinine (CREA), and haemoglobin (Hb) content. Histological and ultrastructural pathological changes in the kidneys were examined through H&E and PAS staining. Kidney tissue levels of interleukin-1β (IL-1β), interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) were determined by ELISA. Expression of the macrophage infiltration and typing as well as that of PEDF, NF-kB, and TLR4 was evaluated in the kidneys.

Results: PEDF was located in glomeruli, and the expression of PEDF protein and mRNA in the kidney of diabetic mice declined significantly. Compared with diabetic mice treated with vehicle, continuous infusion of P78-PEDF could reduce blood urea nitrogen, serum creatinine (CREA), renal macrophage recruitment, inflammatory cytokines, and histological changes and restore the expression of TLR4/NF-κB signalling pathway-related factors in diabetic mice.

Conclusion: These findings highlight the importance of P78-PEDF peptide as a potential treatment in the occurrence and development of diabetic renal injury.


Article available in PDF format

View PDF Download PDF file


  1. Brunton S. Pathophysiology of Type 2 Diabetes: The Evolution of Our Understanding. J Fam Pract. 2016; 65(4 Suppl).
  2. Kolb H, Martin S. Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes. BMC Med. 2017; 15(1): 131.
  3. Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018; 14(2): 88–98.
  4. Klessens CQF, Zandbergen M, Wolterbeek R, et al. Macrophages in diabetic nephropathy in patients with type 2 diabetes. Nephrol Dial Transplant. 2017; 32(8): 1322–1329.
  5. Ismail NA, Abd El Baky AN, Ragab S, et al. Monocyte chemoattractant protein 1 and macrophage migration inhibitory factor in children with type 1 diabetes. J Pediatr Endocrinol Metab. 2016; 29(6): 641–645.
  6. Appari M, Channon KM, McNeill E. Metabolic Regulation of Adipose Tissue Macrophage Function in Obesity and Diabetes. Antioxid Redox Signal. 2018; 29(3): 297–312.
  7. Roma-Lavisse C, Tagzirt M, Zawadzki C, et al. M1 and M2 macrophage proteolytic and angiogenic profile analysis in atherosclerotic patients reveals a distinctive profile in type 2 diabetes. Diab Vasc Dis Res. 2015; 12(4): 279–289.
  8. Zhao Yu, Guo Y, Jiang Y, et al. Mitophagy regulates macrophage phenotype in diabetic nephropathy rats. Biochem Biophys Res Commun. 2017; 494(1-2): 42–50.
  9. Xu J, Rajaratnam R. Cardiovascular safety of non-insulin pharmacotherapy for type 2 diabetes. Cardiovasc Diabetol. 2017; 16(1): 18.
  10. Xie Q, Hao CM, Ji L, et al. ACEI/ARB underused in patients with type 2 diabetes in Chinese population (CCMR-3B study). PLoS One. 2015; 10(2): e0116970.
  11. Pagan-Mercado G, Becerra SP. Signaling Mechanisms Involved in PEDF-Mediated Retinoprotection. Adv Exp Med Biol. 2019; 1185: 445–449.
  12. Ansari D, Althini C, Ohlsson H, et al. The Role of PEDF in Pancreatic Cancer. Anticancer Res. 2019; 39(7): 3311–3315.
  13. Principe DR, DeCant B, Diaz AM, et al. PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction. Oncotarget. 2016; 7(19): 28218–28234.
  14. Wang X, Liu Xu, Ren Y, et al. PEDF protects human retinal pigment epithelial cells against oxidative stress via upregulation of UCP2 expression. Mol Med Rep. 2019; 19(1): 59–74.
  15. Wen H, Liu M, Liu Z, et al. PEDF improves atherosclerotic plaque stability by inhibiting macrophage inflammation response. Int J Cardiol. 2017; 235: 37–41.
  16. Awad AS, Gao T, Gvritishvili A, et al. Protective role of small pigment epithelium-derived factor (PEDF) peptide in diabetic renal injury. Am J Physiol Renal Physiol. 2013; 305(6): F891–F900.
  17. Ishibashi Y, Matsui T, Taira J, et al. Protective Role of PEDF-Derived Synthetic Peptide Against Experimental Diabetic Nephropathy. Horm Metab Res. 2016; 48(9): 613–619.
  18. Rubin A, Salzberg AC, Imamura Y, et al. Identification of novel targets of diabetic nephropathy and PEDF peptide treatment using RNA-seq. BMC Genomics. 2016; 17(1): 936.
  19. Huang B, Miao H, Yuan Y, et al. PEDF decreases cardiomyocyte edema during oxygen‑glucose deprivation and recovery via inhibiting lactate accumulation and expression of AQP1. Int J Mol Med. 2019; 43(5): 1979–1990.
  20. Cheung CYY, Lee CH, Tang CS, et al. Genetic Regulation of Pigment Epithelium-Derived Factor (PEDF): An Exome-Chip Association Analysis in Chinese Subjects With Type 2 Diabetes. Diabetes. 2019; 68(1): 198–206.
  21. Liu X, Liu H, Lu X, et al. PEDF Attenuates Ocular Surface Damage in Diabetic Mice Model Through Its Antioxidant Properties. Curr Eye Res. 2020; 46(3): 302–308.
  22. Yoshida T, Akiba J, Matsui T, et al. Pigment Epithelium-Derived Factor (PEDF) Prevents Hepatic Fat Storage, Inflammation, and Fibrosis in Dietary Steatohepatitis of Mice. Dig Dis Sci. 2017; 62(6): 1527–1536.
  23. Wang JJ, Zhang SX, Lu K, et al. Decreased expression of pigment epithelium-derived factor is involved in the pathogenesis of diabetic nephropathy. Diabetes. 2005; 54(1): 243–250.
  24. Liu Y, Leo LF, McGregor C, et al. Pigment epithelium-derived factor (PEDF) peptide eye drops reduce inflammation, cell death and vascular leakage in diabetic retinopathy in Ins2(Akita) mice. Mol Med. 2012; 18: 1387–1401.
  25. Du Q, Fu YX, Shu AM, et al. Loganin alleviates macrophage infiltration and activation by inhibiting the MCP-1/CCR2 axis in diabetic nephropathy. Life Sci. 2021; 272: 118808.
  26. Li D, Zhu Sw, Liu Dj, et al. Expression of monocyte chemoattractant protein-1 in the pancreas of mice. Chin Med J (Engl). 2005; 118(15): 1269–1273.
  27. Liu P, Li F, Xu X, et al. 1,25(OH)D provides protection against diabetic kidney disease by downregulating the TLR4-MyD88-NF-κB pathway. Exp Mol Pathol. 2020; 114: 104434.
  28. Sanajou D, Haghjo AG, Argani H, et al. FPS-ZM1 and valsartan combination protects better against glomerular filtration barrier damage in streptozotocin-induced diabetic rats. J Physiol Biochem. 2018; 74(3): 467–478.
  29. Al-Rashed F, Ahmad Z, Thomas R, et al. Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α. Sci Rep. 2020; 10(1): 16802.
  30. Ren K, Jiang T, Chen J, et al. PEDF ameliorates macrophage inflammation via NF-κB suppression. Int J Cardiol. 2017; 247: 42.