The Expression of Two Isoforms of Matrix Metalloproteinase-2 in Aged Mouse Models of Diabetes Mellitus and Chronic Kidney Disease

Overview

Journal Kidney Res Clin Pract

Specialty Nephrology

Date 2018 Sep 27

PMID 30254846

Citations 5

Authors

Harin Rhee

Miyeun Han

Sang Soo Kim

Il Young Kim

Hye Won Lee

Sun Sik Bae

Hong Koo Ha

Eun Soon Jung

Min Young Lee

Eun Young Seong

Dong Won Lee

Soo Bong Lee

David H Lovett

Sang Heon Song

Affiliations

Soon will be listed here.

Abstract

Background: This study was undertaken to explore the effects of aging on the kidneys in mouse models of diabetes and chronic kidney disease (CKD), and to compare the expression of two isoforms of matrix metalloproteinase-2 (MMP-2)-secretory full-length MMP-2 and intracellular N-terminal truncated MMP-2 (NTT-MMP-2)-in these models.

Methods: Two experimental ICR mouse models were used: a streptozotocin (STZ)-induced type 1 diabetes mellitus model and a 5/6 nephrectomized (5/6Nx) CKD model. The abundance of each isoform of MMP-2 was determined by quantitative polymerase chain reaction (qPCR), and functional analyses were conducted. Moreover, the protein levels of the two MMP-2 isoforms were determined semi-quantitatively by immunohistochemical staining, and their association with tissue damage was assessed.

Results: Both isoforms of MMP-2 were upregulated in the kidney tissues of STZ-induced diabetic mice and 5/6Nx mice, irrespective of age. Characteristically, NTT-MMP-2 protein expression was elevated in old control mice, in line with the qPCR results. NTT-MMP-2 expression was limited to the renal cortex, and to the tubulointerstitial area rather than the glomerular area. In terms of tissue damage, tubulointerstitial fibrosis was more severe in old 5/6Nx mice than in their young counterparts, whereas glomerulosclerosis was comparable in old and young 5/6Nx mice.

Conclusion: The intracellular isoform of MMP-2 was induced by ageing, irrespective of the presence of diabetes or CKD, and its induction may be related to tubulointerstitial fibrosis in chronic kidney disease.

Citing Articles

Effects of Polysaccharides on the Functions of Human Skin Fibroblasts and Expression of Matrix Metalloproteinase-2 under High-Glucose Conditions.

Li Y, Cao Z, Li Q, Wang C, Zhou Z Int J Endocrinol. 2021; 2021:1092975.

PMID: 33777140 PMC: 7969111. DOI: 10.1155/2021/1092975.

Epigenetic Regulation of the N-Terminal Truncated Isoform of Matrix Metalloproteinase-2 (NTT-MMP-2) and Its Presence in Renal and Cardiac Diseases.

de Oliveira Cruz J, Silva A, Ribeiro J, Luizon M, Ceron C Front Genet. 2021; 12:637148.

PMID: 33732288 PMC: 7959838. DOI: 10.3389/fgene.2021.637148.

Pyrrolidine dithiocarbamate reduces alloxan-induced kidney damage by decreasing nox4, inducible nitric oxide synthase, and metalloproteinase-2.

Pereira B, do Valle G, Salles B, Costa K, Angelo M, Torres L Naunyn Schmiedebergs Arch Pharmacol. 2020; 393(10):1899-1910.

PMID: 32440769 DOI: 10.1007/s00210-020-01906-1.

Inhibition of p300/CBP-Associated Factor Attenuates Renal Tubulointerstitial Fibrosis through Modulation of NF-kB and Nrf2.

Chung S, Kim S, Son M, Kim M, Koh E, Shin S Int J Mol Sci. 2019; 20(7).

PMID: 30925687 PMC: 6479343. DOI: 10.3390/ijms20071554.

Effects of Resveratrol on the Renin-Angiotensin System in the Aging Kidney.

Jang I, Kim E, Lim J, Kim M, Ban T, Yoon H Nutrients. 2018; 10(11).

PMID: 30424556 PMC: 6267480. DOI: 10.3390/nu10111741.

References

Baker D, Childs B, Durik M, Wijers M, Sieben C, Zhong J . Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016; 530(7589):184-9. PMC: 4845101. DOI: 10.1038/nature16932. View

Oberg B, McMenamin E, Lucas F, McMonagle E, Morrow J, Ikizler T . Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney Int. 2004; 65(3):1009-16. DOI: 10.1111/j.1523-1755.2004.00465.x. View

Chandran G, Sirajudeen K, Yusoff N, Swamy M, Samarendra M . Effect of the antihypertensive drug enalapril on oxidative stress markers and antioxidant enzymes in kidney of spontaneously hypertensive rat. Oxid Med Cell Longev. 2014; 2014:608512. PMC: 4164806. DOI: 10.1155/2014/608512. View

Cheng S, Pollock A, Mahimkar R, Olson J, Lovett D . Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury. FASEB J. 2006; 20(11):1898-900. DOI: 10.1096/fj.06-5898fje. View

Elsherbiny H, Alexander M, Kremers W, Park W, Poggio E, Prieto M . Nephron hypertrophy and glomerulosclerosis and their association with kidney function and risk factors among living kidney donors. Clin J Am Soc Nephrol. 2014; 9(11):1892-902. PMC: 4220756. DOI: 10.2215/CJN.02560314. View

Rule A, Amer H, Cornell L, Taler S, Cosio F, Kremers W . The association between age and nephrosclerosis on renal biopsy among healthy adults. Ann Intern Med. 2010; 152(9):561-7. PMC: 2864956. DOI: 10.7326/0003-4819-152-9-201005040-00006. View

Lovett D, Mahimkar R, Raffai R, Cape L, Maklashina E, Cecchini G . A novel intracellular isoform of matrix metalloproteinase-2 induced by oxidative stress activates innate immunity. PLoS One. 2012; 7(4):e34177. PMC: 3317925. DOI: 10.1371/journal.pone.0034177. View

Verzola D, Gandolfo M, Gaetani G, Ferraris A, Mangerini R, Ferrario F . Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy. Am J Physiol Renal Physiol. 2008; 295(5):F1563-73. DOI: 10.1152/ajprenal.90302.2008. View

Jin D, Yun S, Lee S, Han S, Kim W, Park J . Current characteristics of dialysis therapy in Korea: 2015 registry data focusing on elderly patients. Kidney Res Clin Pract. 2016; 35(4):204-211. PMC: 5142391. DOI: 10.1016/j.krcp.2016.09.006. View

10.

Thiab N, King N, Jones G . Effect of ageing and oxidative stress on antioxidant enzyme activity in different regions of the rat kidney. Mol Cell Biochem. 2015; 408(1-2):253-60. DOI: 10.1007/s11010-015-2503-2. View

11.

Flatt T . A new definition of aging?. Front Genet. 2012; 3:148. PMC: 3425790. DOI: 10.3389/fgene.2012.00148. View

12.

Ceron C, Baligand C, Joshi S, Wanga S, Cowley P, Walker J . An intracellular matrix metalloproteinase-2 isoform induces tubular regulated necrosis: implications for acute kidney injury. Am J Physiol Renal Physiol. 2017; 312(6):F1166-F1183. PMC: 5495883. DOI: 10.1152/ajprenal.00461.2016. View

13.

Forbes J, Coughlan M, Cooper M . Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes. 2008; 57(6):1446-54. DOI: 10.2337/db08-0057. View

14.

Sturmlechner I, Durik M, Sieben C, Baker D, van Deursen J . Cellular senescence in renal ageing and disease. Nat Rev Nephrol. 2016; 13(2):77-89. DOI: 10.1038/nrneph.2016.183. View

15.

De Vecchi A, Bamonti F, Novembrino C, Ippolito S, Guerra L, Lonati S . Free and total plasma malondialdehyde in chronic renal insufficiency and in dialysis patients. Nephrol Dial Transplant. 2009; 24(8):2524-9. DOI: 10.1093/ndt/gfp102. View

16.

Tan J, Busque S, Workeneh B, Ho B, Derby G, Blouch K . Effects of aging on glomerular function and number in living kidney donors. Kidney Int. 2010; 78(7):686-92. PMC: 3353650. DOI: 10.1038/ki.2010.128. View

17.

Kim S, Shin N, Bae S, Lee M, Rhee H, Kim I . Enhanced expression of two discrete isoforms of matrix metalloproteinase-2 in experimental and human diabetic nephropathy. PLoS One. 2017; 12(2):e0171625. PMC: 5298282. DOI: 10.1371/journal.pone.0171625. View

18.

Yang H, Fogo A . Cell senescence in the aging kidney. J Am Soc Nephrol. 2010; 21(9):1436-9. DOI: 10.1681/ASN.2010020205. View

19.

Clements M, Chaber C, Ledbetter S, Zuk A . Increased cellular senescence and vascular rarefaction exacerbate the progression of kidney fibrosis in aged mice following transient ischemic injury. PLoS One. 2013; 8(8):e70464. PMC: 3734312. DOI: 10.1371/journal.pone.0070464. View