Article | Published:

SND p102 promotes extracellular matrix accumulation and cell proliferation in rat glomerular mesangial cells via the AT1R/ERK/Smad3 pathway

Acta Pharmacologica Sinicavolume 39pages15131521 (2018) | Download Citation

Subjects

Abstract

SND p102 was first described as a transcriptional co-activator, and subsequently determined to be a co-regulator of Pim-1, STAT6 and STAT5. We previously reported that SND p102 expression was increased in high glucose-treated mesangial cells (MCs) and plays a role in the extracellular matrix (ECM) accumulation of MCs by regulating the activation of RAS. In this study, we further examined the roles of SND p102 in diabetic nephropathy (DN)-induced glomerulosclerosis. Rats were injected with STZ (50 mg/kg, ip) to induce diabetes. MCs or isolated glomeruli were cultured in normal glucose (NG, 5.5 mmol/L)- or high glucose (HG, 25 mmol/L)-containing DMEM. We found that SND p102 expression was significantly increased in the diabetic kidneys, as well as in HG-treated isolated glomeruli and MCs. In addition, HG treatment induced significant fibrotic changes in MCs evidenced by enhanced protein expression of TGF-β, fbronectin and collagen IV, and significantly increased the proliferation of MCs. We further revealed that overexpression of SND p102 significantly increased the protein expression of angiotensin II (Ang II) type 1 receptor (AT1R) in MCs by increasing its mRNA levels via directly targeting the AT1R 3′-UTR, which resulted in activation of the ERK/Smad3 signaling and subsequently promoted the up-regulation of fbronectin, collagen IV, and TGF-β in MCs, as well as the cell proliferation. These results demonstrate that SND p102 is a key regulator of AT1R-mediating ECM synthesis and cell proliferation in MCs. Thus, small molecule inhibitors of SND p102 may be a novel therapeutic strategy for DN.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Kitada M, Ogura Y, Monno I, Koya D. Regulating autophagy as a therapeutic target for diabetic nephropathy. Curr Diab Rep 2017; 17: 53.

  2. 2

    Mauer M, Caramori ML, Fioretto P, Najafian B. Glomerular structural-functional relationship models of diabetic nephropathy are robust in type 1 diabetic patients. Nephrol Dial Transplant 2015; 30: 918–23.

  3. 3

    Cao Z, Cooper ME. Pathogenesis of diabetic nephropathy. J Diabetes Investig 2011; 2: 243–7.

  4. 4

    Yacoub R, Campbell KN. Inhibition of RAS in diabetic nephropathy. Int J Nephrol Renovasc Dis 2015; 8: 29–40.

  5. 5

    Ferrao FM, Lara L S, Lowe J. Renin-angiotensin system in the kidney: What is new? World J Nephrol 2014; 3: 64–76.

  6. 6

    Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 2002; 277: 14838–43.

  7. 7

    Koka V, Huang XR, Chung AC, Wang W, Truong LD, Lan HY. Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. Am J Pathol 2008; 172: 1174–83.

  8. 8

    Xue H, Zhou L, Yuan P, Wang Z, Ni J, Yao T, et al. Counteraction between angiotensin II and angiotensin-(1-7) via activating angiotensin type I and Mas receptor on rat renal mesangial cells. Regul Pept 2012; 177: 12–20.

  9. 9

    Lopez-Hernandez FJ, Lopez-Novoa JM. Role of TGF-beta in chronic kidney disease: an integration of tubular, glomerular and vascular effects. Cell Tissue Res 2012; 347: 141–54.

  10. 10

    Lan HY. Diverse roles of TGF-beta/Smads in renal fibrosis and inflammation. Int J Biol Sci 2011; 7: 1056–67.

  11. 11

    Meng XM, Tang PM, Li J, Lan HY. TGF-beta/Smad signaling in renal fibrosis. Front Physiol 2015; 6: 82.

  12. 12

    Chen HY, Huang XR, Wang W, Li JH, Heuchel RL, Chung AC, et al. The protective role of Smad7 in diabetic kidney disease: mechanism and therapeutic potential. Diabetes 2011; 60: 590–601.

  13. 13

    Mauer M, Zinman B, Gardiner R, Drummond KN, Suissa S, Donnelly SM, et al. ACE-I and ARBs in early diabetic nephropathy. J Renin Angiotensin Aldosterone Syst 2002; 3: 262–9.

  14. 14

    Jacobsen P, Andersen S, Jensen BR, Parving HH. Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. J Am Soc Nephrol 2003; 14: 992–9.

  15. 15

    Mohamed RH, Abdel-Aziz HR, Abd EMD, Abd ET. Effect of RAS inhibition on TGF-beta, renal function and structure in experimentally induced diabetic hypertensive nephropathy rats. Biomed Pharmacother 2013; 67: 209–14.

  16. 16

    Wang C, Min C, Rong X, Fu T, Huang X, Wang C. Irbesartan can improve blood lipid and the kidney function of diabetic nephropathy. Discov Med 2015; 20: 67–77.

  17. 17

    Tong X, Drapkin R, Yalamanchili R, Mosialos G, Kieff E. The Epstein-Barr virus nuclear protein 2 acidic domain forms a complex with a novel cellular coactivator that can interact with TFIIE. Mol Cell Biol 1995; 15: 4735–44.

  18. 18

    Palacios L, Ochoa B, Gomez-Lechon M J, Castell JV, Fresnedo O. Overexpression of SND p102, a rat homologue of p100 coactivator, promotes the secretion of lipoprotein phospholipids in primary hepatocytes. Biochim Biophys Acta 2006; 1761: 698–708.

  19. 19

    Callebaut I, Mornon JP. The human EBNA-2 coactivator p100: multidomain organization and relationship to the staphylococcal nuclease fold and to the tudor protein involved in Drosophila melanogaster development. Biochem J 1997; 321: 125–32.

  20. 20

    Caudy AA, Ketting RF, Hammond SM, Denli AM, Bathoorn AM, Tops BB, et al. A micrococcal nuclease homologue in RNAi effector complexes. Nature 2003; 425: 411–4.

  21. 21

    Jariwala N, Rajasekaran D, Srivastava J, Gredler R, Akiel MA, Robertson CL, et al. Role of the staphylococcal nuclease and tudor domain containing 1 in oncogenesis. Int J Oncol 2015; 46: 465–73.

  22. 22

    Rajasekaran D, Jariwala N, Mendoza RG, Robertson CL, Akiel M A, Dozmorov M, et al. Staphylococcal nuclease and tudor domain containing 1 (SND1 Protein) promotes hepatocarcinogenesis by inhibiting monoglyceride lipase (MGLL). J Biol Chem 2016; 291: 10736–46.

  23. 23

    Yang F, Chung AC, Huang XR, Lan HY. Angiotensin II induces connective tissue growth factor and collagen I expression via transforming growth factor-beta-dependent and -independent Smad pathways: the role of Smad3. Hypertension 2009; 54: 877–84.

  24. 24

    Wang Z, Ni J, Shao D, Liu J, Shen Y, Zhou L, et al. Elevated transcriptional co-activator p102 mediates angiotensin II type 1 receptor up-regulation and extracellular matrix overproduction in the high glucose-treated rat glomerular mesangial cells and isolated glomeruli. Eur J Pharmacol 2013; 702: 208–17.

  25. 25

    Kong Y L, Shen Y, Ni J, Shao D C, Miao N J, Xu J L, et al. Insulin deficiency induces rat renal mesangial cell dysfunction via activation of IGF-1/IGF-1R pathway. Acta Pharmacol Sin 2016; 37: 217–27.

  26. 26

    He M, Zhang L, Shao Y, Xue H, Zhou L, Wang XF, et al. Angiotensin II type 2 receptor mediated angiotensin II and high glucose induced decrease in renal prorenin/renin receptor expression. Mol Cell Endocrinol 2010; 315: 188–94.

  27. 27

    Ponchiardi C, Mauer M, Najafian B. Temporal profile of diabetic nephropathy pathologic changes. Curr Diab Rep 2013; 13: 592–9.

  28. 28

    Dalla VM, Saller A, Mauer M, Fioretto P. Role of mesangial expansion in the pathogenesis of diabetic nephropathy. J Nephrol 2001; 14 Suppl 4: S51–7.

  29. 29

    Ellis EN, Warady BA, Wood EG, Hassanein R, Richardson WP, Lane PH, et al. Renal structural-functional relationships in early diabetes mellitus. Pediatr Nephrol 1997; 11: 584–91.

  30. 30

    Burns KD. Angiotensin II and its receptors in the diabetic kidney. Am J Kidney Dis 2000; 36: 449–67.

  31. 31

    Kennefick TM, Anderson S. Role of angiotensin II in diabetic nephropathy. Semin Nephrol 1997; 17: 441–7.

  32. 32

    Leverson JD, Koskinen PJ, Orrico FC, Rainio EM, Jalkanen KJ, Dash AB, et al. Pim-1 kinase and p100 cooperate to enhance c-Myb activity. Mol Cell 1998; 2: 417–25.

  33. 33

    Valineva T, Yang J, Palovuori R, Silvennoinen O. The transcriptional co-activator protein p100 recruits histone acetyltransferase activity to STAT6 and mediates interaction between the CREB-binding protein and STAT6. J Biol Chem 2005; 280: 14989–96.

  34. 34

    Paukku K, Yang J, Silvennoinen O. Tudor and nuclease-like domains containing protein p100 function as coactivators for signal transducer and activator of transcription 5. Mol Endocrinol 2003; 17: 1805–14.

  35. 35

    Paukku K, Kalkkinen N, Silvennoinen O, Kontula K K, Lehtonen JY. p100 increases AT1R expression through interaction with AT1R 3′-UTR. Nucleic Acids Res 2008; 36: 4474–87.

Download references

This research was financially supported by the National Natural Science Foundation of China (No 81470591 and 81670664 to Li-min LU; No 81400695 to De-cui SHAO). This work was also supported by the Science and Technology Commission of Shanghai Municipality (14DZ2260200, the project of Shanghai Key Laboratory of Kidney and Blood Purification). All authors declare that no conflicts of interest exist.

Author information

Author notes

  1. These authors contributed equally to this work.

Affiliations

  1. Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    • Jin-lan Xu
    • , Xin-xin Gan
    • , Jun Ni
    • , De-cui Shao
    • , Yang Shen
    • , Nai-jun Miao
    • , Dan Xu
    • , Li Zhou
    • , Wei Zhang
    •  & Li-min Lu
  2. Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    • Jun Ni
  3. Cell Electrophysiology Laboratory, Wannan Medical College, Wuhu, 241002, China

    • De-cui Shao

Authors

  1. Search for Jin-lan Xu in:

  2. Search for Xin-xin Gan in:

  3. Search for Jun Ni in:

  4. Search for De-cui Shao in:

  5. Search for Yang Shen in:

  6. Search for Nai-jun Miao in:

  7. Search for Dan Xu in:

  8. Search for Li Zhou in:

  9. Search for Wei Zhang in:

  10. Search for Li-min Lu in:

Corresponding authors

Correspondence to Wei Zhang or Li-min Lu.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/aps.2017.184