THE CONTENT OF DDR1 COLLAGEN RECEPTORS IN THE BLOOD SERUM OF CHILDREN WITH CHRONIC PYELONEPHRITIS: CONNECTION WITH THE URODYNAMICS DISRUPTION AND METABOLIC DISORDERS

THE AIM to determine the level of DDR1 collagen receptors in the blood serum of children with chronic pyelonephritis (CP), depending on its forms. PATIENTS AND METHODS. 306 patients with CP in the stage of clinical and laboratory remission were examined. Age of patients is 6 to 16 years. In the structure of CP (p< 0,01) 246 (80,39%) patients predominated with secondary CP (SCP). There were 183 (74,39%) children with secondary obstructive CP (SOCP) and 63 (25,61%) children with secondary dysmetabolic CP (SDCP). 60 (19,61%) children suffered from primary CP (PCP). Human Discoidin Domain Receptors (DDR1) was determined in the blood serum by using a standard kit (TSZ Eliza, USA). RESULTS. DDR1 level increase (р<0,01) was determined in the blood serum of patients with SCP. Patients with PCP showed the collagen receptors level within reference values. Statistically significant difference of DDR1 blood serum values between patients with SOCP and SDCP (р><0,01) was determined. It was significantly higher than normal values by patients with SOCP, and within the conditional norm by patients with SDCP. The high->< 0,01) was determined in the blood serum of patients with SCP. Patients with PCP showed the collagen receptors level within reference values. Statistically significant difference of DDR1 blood serum values between patients with SOCP and SDCP (р< 0,01) was determined. It was significantly higher than normal values by patients with SOCP, and within the conditional norm by patients with SDCP. The high- est DDR1 concentrations was detected by children with vesicoureteral reflux (VUR) in the anamnesis. These values significantly exceeded not only the reference values, but also the level of DDR1 by patients with SOCP with a background of other obstructive uropathies (р< 0,001). CONCLUSION. The study of DDR1 is a promising direction aimed at preclinical diagnostics of structural changes in tubulointerstitial, associated with latent inflammatory process and sclerosing, by patients with SOCP.

1. Papaian AV, Savenkova ND (red.). Clinicheskaia nefrologiia detskogo vozrasta. Rukovodstvo dlia vrachej. Levsha, SPb., 2008; 600

2. Ignatova MS. Modern problems of nephrology in childhood. Nephrology and dialysis 2011; 13(2):66–75

3. Kiseleva T, Brenner D. Fibrogenesis of parenchymal organs. Proc Am Thorac Soc 2008; 5(3):342–349. doi: 10.1513/ pats.200711-168DR

4. Chatziantoniou C Dussaule JC. Insights into the mechanisms of renal fibrosis: is it possible to achieve regression? Am J Physiol Renal Physiol 2005; 289: F227–F234. Doi: 10.1152/ ajprenal.00453.2004

5. Hubbard SR, Mohammadi M, Schlessinger J. Autoregulatory mechanisms in protein-tyrosine kinases. J Biol Chem 1998; 273(20):11987–11990. PMID:9575136

6. Agarwal G Mihai C Iscru DF. Interaction of discoidin domain receptor 1 with collagen type 1. J Mol Biol 2007; 367(2): 443–455. DOI: 10.1016/j.jmb.2006.12.073

7. Meyer zum Gottesberge AM, Gross O, Becker-Lendzian U, et al. Inner ear defects and hearing loss in mice lacking the collagen receptor DDR1. Lab invest 2008; 88(1):27–37. Doi: 10.1038/ labinvest.3700692

8. Vogel WF, Abdulhussein R, Ford CE. Sensing extracellular matrix: an update on discoidin domain receptor function. Cell Signal 2006; 18(8):1108–1116. Doi: 10.1016/j.cellsig.2006.02.012

9. Alves F, Saupe S, Ledwon M et al. Identification of two novel, kinase-deficient variants of discoidin domain receptor 1: differential expression in human colon cancer cell lines. FASEB J 2001; 15(7):1321–1323. PMID: 11344127

10. Chatziantoniou C, Dussaule JC. Is Kidney iniury a reversible process? Current Opinion in Nephrolodgy and Hypertension 2008 Jan; 17(1):76–81. DOI: 10.1097/MNH.0b013e3282f1bb69

11. Yeh YC, Wu CC, Wang YK, Tang MJ. DDR1 triggers epithelial cell differentiation by promoting cell adhesion through stabilization of E-cadherin. Mol Biol Cell 2011; 22(7):940–953. Doi: 10.1091/ mbc.E10-08-0678

12. Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1997; 1(1):13–23. PMID: 9659899

13. Alfieri C, Dorison A, Kerroch M et al. Silencing discoidin domain receptor: a novel approach to reverse the progression of glomerulonephritis. Nephrol Dial Transplant Abstracts of the 49th ERA-EDTA (European Renal Association – European Dialysis and Transplant Association) Congress. (May 24–27, 2012. Paris, France). 2012; 27(2):1144–1145

14. Guerrot D, Kerroch M, Placier S et al. Discoidin domain receptor 1 is a major mediator of inflammation and fibrosis in obstructive nephropathy. Am J Pathol 2011; 179(1):83–91. Doi: 10.1016/j.ajpath.2011.03.023

15. Flamant M, Placier S, Rodenas A et al. Discoidin domain receptor 1 null mice are protected against hypertension-induced renal disease. J Am Soc Nephrol 2006; 17(12):3374–3381. Doi: 10.1681/ASN.2006060677

16. Wang CZ, Hsu YM, Tang MJ. Function of discoidin domain receptor I in HGF-induced branching tubulogenesis of MDCK cells in collagen gel. J Cell Physiol 2005;203(1):295–304. Doi: 10.1002/jcp.20227

17. Matsuyama W, Kamohara H, Galligan C et al. Interaction of discoidin domain receptor 1 isoform b (DDR1b) with collagen activates p38 mitogen-activated protein kinase and promotes differentiation of macrophages. Faseb J 2003;17(10):1286–1288. Doi: 10.1096/fj.02-0320fje

18. Kerroch, M. Alferi C, Dorison A et al. Protective effects of genetic inhibition of Discoidin Domain Receptor 1 in experimental renal disease. Sci Rep 6, 21262 (2016). doi: 10.1038/srep21262

19. Kerroch M, Guerrot D, Vandermeersch S et al Genetic inhibition of discoidin domain receptor 1 protects mice against crescentic glomerulonephritis. FASEB J 2012; 26(10):4079–4091. doi: 10.1096/fj.11-194902

20. Li Y, Lu X, Ren X, Ding K. Small molecule discoidin domain receptor kinase inhibitors and potential medical applications. J Med Chem 2015; 58(8):3287–3301. doi: 10.1021/jm5012319

21. Murray CW, Berdini V, Buck IM et al. Fragment-based discovery of potent and selective DDR1/2 inhibitors. ACS Med Chem Lett 2015; 6(7):798–803. doi: 10.1021/acsmedchemlett.5b00143

22. Chatziantoniou C, Dorison A, Dussaule JC. DDR1 in Renal Function and Disease. In: Fridman R., Huang P. (eds) Discoidin Domain Receptors in Health and Disease. Springer, New York, NY, 2016; 281–291

23. Leonova LV. Patologicheskaya anatomiya vrozhdennykh obstruktivnykh uropatii u detei: avtoref. dis. … d-ra med. Nauk, M., 2009; 55

24. Razin MP, Lavrov OV, Razin AP. Stressornye izmeneniya immunologicheskoi reaktivnosti u detei s vrozhdennymi obstruktivnymi uropatiyami. Fundamental’nye issledovaniya. 2007;5:52–52] URL: https://www.fundamental-research.ru/ru/article/view?id=3105 (дата обращения: 16.11.2017)

25. Vozianov AF, Majdannik VG, Bidnyj VG, Bagdasarova IV. Osnovy nefrologii detskogo vozrasta. Kniga plius, K., 2002; 348

26. Dlin VV, Osmanov IM. Dysmetabolic nephropathy with calcium oxalate crystalluria. Effektivnaya farmakoterapiya 2013;4:8–16] URL: http://umedp.ru/articles/dismetabolicheskaya_nefropatiya_s_oksalatnokaltsievoy_ kristalluriey.html (дата обращения: 16.11.2017)

27. Zubarenko AV, Stoeva TV. Dismetabolicheskaya nefropatiya v pediatricheskoi praktike. Soobshchenie 2. Printsipy lecheniya i profilaktiki. Zdorov’e rebenka 2011; 3(30):97–104] URL: http://www.mif-ua.com/archive/article/21929 (дата обращения: 16.11.2017)

28. Paunova SS. Patogeneticheskie osnovy formirovanija refljuks-nefropatii u detej: Avtoref. dis. … d-ra med nauk, M., 2004; 44

29. Zorin IV, Vyalkova AA. Prediction of progression of tubulointerstitial damage in children with reflux nephropathy. Nephrology (Saint-Petersburg). 2015;19(3):65–71. (In Russ.)] URL: http:// journal.nephrolog.ru/jour/article/view/99 (дата обращения: 16.11.2017)

30. Slobodian EI, Kaladze NN, Govdalyuk AL, Bodnaryuk IV. Cytokine profile and human discoidin domain receptors 1 in children with chronic pyelonephritis. Russian Journal of Immunology 2015; 9(18), 3(1): 202–204 (in Russ.)