nach oben

Clinical and Experimental Nephrology

Erschienen in:

16.02.2018 | Original article

Semaphorin 7A in circulating regulatory T cells is increased in autosomal-dominant polycystic kidney disease and decreases with tolvaptan treatment

Erschienen in: Clinical and Experimental Nephrology | Ausgabe 4/2018

Einloggen, um Zugang zu erhalten

Abstract

Background

Semaphorin 7A (SEMA7A) is an immunomodulating protein implicated in lung and liver fibrosis. In autosomal-dominant polycystic kidney disease (ADPKD), the progressive expansion of renal cysts, inflammation, and subsequent renal fibrosis leads to end-stage renal disease (ESRD). SEMA7A may play a role in renal fibrosis and in ADPKD.

Methods

We evaluated Sema7a in a mouse model of renal fibrosis and determined the expression of SEMA7A in human ADPKD kidney. We analyzed SEMA7A expression on peripheral blood mononuclear cells (PBMCs), including CD45⁺ (leukocyte), CD14⁺(monocyte), CD4+ (T lymphocytes) and CD4⁺Foxp3⁺CD25⁺ [regulatory T lymphocytes (Tregs)] from 90 ADPKD patients (11 tolvaptan treated and 79 tolvaptan naïve), and 21 healthy volunteers, using a Fluorescence-Activated Cell Sorting (FACS).

Results

Sema7a is required for renal fibrosis. SEMA7A shows robust expression in ADPKD kidneys, localizing to cysts derived from distal tubules. SEMA7A is higher in circulating monocytes, but unchanged in CD4⁺ lymphocytes in ADPKD patients. The SEMA7A increase was detected early (stage 1 CKD) and seemed more prominent in patients with smaller kidneys (p = 0.09). Compared to tolvaptan-naïve ADPKD patients, those treated with tolvaptan showed reduced SEMA7A expression on monocytes, T lymphocytes, and Tregs, although the number of PBMCs was unchanged. After 1 month of tolvaptan treatment, SEMA7A expression on Tregs decreased.

Conclusions

SEMA7A shows potential as both a therapeutic target in mammalian kidney fibrosis and as a marker of inflammation in ADPKD patients. SEMA7A expression was lower after tolvaptan treatment, which may reflect drug efficacy.

Wilson PD. Polycystic kidney disease. N Engl J Med 2004;350: 151–64.CrossRefPubMed

Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San Millan JL, Gamble V, Harris PC. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet 1995;10:151–60.CrossRefPubMed

Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science. 1996;272:1339–42.CrossRefPubMed

Chen L, Zhou X, Fan LX, Yao Y, Swenson-Fields KI, Gadjeva M, Wallace DP, Peters DJ, Yu A, Grantham JJ, Li X. Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease. J Clin Invest 2015;125:2399–412.CrossRefPubMedPubMedCentral

Karihaloo A, Koraishy F, Huen SC, Lee Y, Merrick D, Caplan MJ, Somlo S, Cantley LG. Macrophages promote cyst growth in polycystic kidney disease. J Am Soc Nephrol. 2011;22:1809–14.CrossRefPubMedPubMedCentral

Swenson-Fields KI, Vivian CJ, Salah SM, Peda JD, Davis BM, van Rooijen N, Wallace DP, Fields TA. Macrophages promote polycystic kidney disease progression. Kidney Int 2013;83:855–64.CrossRefPubMedPubMedCentral

Gardner KD Jr, Burnside JS, Elzinga LW, Locksley RM. Cytokines in fluids from polycystic kidneys. Kidney Int 1991;39: 718–24.CrossRefPubMed

Zheng D, Wolfe M, Cowley BD Jr, Wallace DP, Yamaguchi T, Grantham JJ. Urinary excretion of monocyte chemoattractant protein-1 in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2003;14:2588–95.CrossRefPubMed

Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Dandurand A, Ouyang J, Czerwiec FS, Blais JD. Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial. Nephrol Dial Transpl. 2017;1–13.

10.

Grantham JJ, Chapman AB, Blais J, Czerwiec FS, Devuyst O, Gansevoort RT, Higashihara E, Krasa H, Zhou W, Ouyang J, Perrone RD, Torres VE. Tolvaptan suppresses monocyte chemotactic protein-1 excretion in autosomal-dominant polycystic kidney disease. Nephrol Dial Transpl. 2017;32:969–75.

11.

Ishikawa M, Kobayashi N, Sugiyama F, Onoda S, Ishimitsu T. Renoprotective effect of vasopressin v2 receptor antagonist tolvaptan in Dahl rats with end-stage heart failure. Int Heart J. 2013;54:98–106.CrossRefPubMed

12.

Yamazaki T, Izumi Y, Nakamura Y, Yamashita N, Fujiki H, Osada-Oka M, Shiota M, Hanatani A, Shimada K, Iwao H, Yoshiyama M. Tolvaptan improves left ventricular dysfunction after myocardial infarction in rats. Circ Heart Fail. 2012;5:794–802.CrossRefPubMed

13.

Yamazaki T, Nakamura Y, Shiota M, Osada-Oka M, Fujiki H, Hanatani A, Shimada K, Miura K, Yoshiyama M, Iwao H, Izumi Y. Tolvaptan attenuates left ventricular fibrosis after acute myocardial infarction in rats. J Pharmacol Sci. 2013;123:58–66.CrossRefPubMed

14.

Ikeda T, Iwanaga Y, Watanabe H, Morooka H, Akahoshi Y, Fujiki H, Miyazaki S. Effects of long-term blockade of vasopressin receptor types 1a and 2 on cardiac and renal damage in a rat model of hypertensive heart failure. J Cardiovasc Pharmacol 2015;66: 487–96.CrossRefPubMed

15.

Song X, Di Giovanni V, He N, Wang K, Ingram A, Rosenblum ND, Pei Y. Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks. Hum Mol Genet. 2009;18:2328–43.CrossRefPubMed

16.

Menon V, Rudym D, Chandra P, Miskulin D, Perrone R, Sarnak M. Inflammation, oxidative stress, and insulin resistance in polycystic kidney disease. Clin J Am Soc Nephrol. 2011;6:7–13.CrossRefPubMedPubMedCentral

17.

Kocyigit I, Eroglu E, Orscelik O, Unal A, Gungor O, Ozturk F, Karakukcu C, Imamoglu H, Sipahioglu MH, Tokgoz B, Oymak O. Pentraxin 3 as a novel bio-marker of inflammation and endothelial dysfunction in autosomal dominant polycystic kidney disease. J Nephrol. 2014;27:181–6.CrossRefPubMed

18.

Yamada A, Kubo K, Takeshita T, Harashima N, Kawano K, Mine T, Sagawa K, Sugamura K, Itoh K. Molecular cloning of a glycosylphosphatidylinositol-anchored molecule CDw108. J Immunol 1999;162:4094–100.PubMed

19.

Garcia-Areas R, Libreros S, Iragavarapu-Charyulu V. Semaphorin7A: branching beyond axonal guidance and into immunity. Immunol Res 2013;57:81–5.CrossRefPubMedPubMedCentral

20.

Pasterkamp RJ, Peschon JJ, Spriggs MK, Kolodkin AL. Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature. 2003;424:398–405.CrossRefPubMed

21.

Delorme G, Saltel F, Bonnelye E, Jurdic P, Machuca-Gayet I. Expression and function of semaphorin 7A in bone cells. Biol Cell 2005;97:589–97.CrossRefPubMed

22.

Kang HR, Lee CG, Homer RJ, Elias JA. Semaphorin 7A plays a critical role in TGF-beta1-induced pulmonary fibrosis. J Exp Med. 2007;204:1083–93.CrossRefPubMedPubMedCentral

23.

Suzuki K, Okuno T, Yamamoto M, Pasterkamp RJ, Takegahara N, Takamatsu H, Kitao T, Takagi J, Rennert PD, Kolodkin AL, Kumanogoh A, Kikutani H. Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin. Nature. 2007;446:680–4.CrossRefPubMed

24.

Reilkoff RA, Peng H, Murray LA, Peng X, Russell T, Montgomery R, Feghali-Bostwick C, Shaw A, Homer RJ, Gulati M, Mathur A, Elias JA, Herzog EL. Semaphorin 7a + regulatory T cells are associated with progressive idiopathic pulmonary fibrosis and are implicated in transforming growth factor-beta1-induced pulmonary fibrosis. Am J Respir Crit Care Med. 2013;187:180–8.CrossRefPubMedPubMedCentral

25.

Gan Y, Reilkoff R, Peng X, Russell T, Chen Q, Mathai SK, Homer R, Gulati M, Siner J, Elias J, Bucala R, Herzog E. Role of semaphorin 7a signaling in transforming growth factor β1–induced lung fibrosis and scleroderma-related interstitial lung disease. Arthritis Rheum. 2011;63:2484–94.CrossRefPubMedPubMedCentral

26.

De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Trozzi L, Candelaresi C, Bataller R, Millan C, Brenner DA, Vivarelli M, Mocchegiani F, Marzioni M, Benedetti A, Svegliati-Baroni G. Semaphorin 7A contributes to TGF-beta-mediated liver fibrogenesis. The Am J Pathol 2013;183:820–30.CrossRefPubMed

27.

Grantham JJ, Mulamalla S, Swenson-Fields KI. Why kidneys fail in autosomal dominant polycystic kidney disease. Nat Rev Nephrol 2011;7:556–66.CrossRefPubMed

28.

Yuan A, Lee Y, Choi U, Moeckel G, Karihaloo A. Chemokine receptor Cxcr4 contributes to kidney fibrosis via multiple effectors. Am J Physiol Renal Physiol. 2015;308:F459–72.CrossRef

29.

Pei Y, Obaji J, Dupuis A, Paterson AD, Magistroni R, Dicks E, Parfrey P, Cramer B, Coto E, Torra R, San Millan JL, Gibson R, Breuning M, Peters D, Ravine D. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol 2009;20: 205–12.CrossRefPubMedPubMedCentral

30.

Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang J, McQuade RD, Blais JD, Czerwiec FS, Sergeyeva O. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med. 2017;377:1930–42.CrossRefPubMed

31.

Boertien WE, Meijer E, de Jong PE, ter Horst GJ, Renken RJ, van der Jagt EJ, Kappert P, Ouyang J, Engels GE, van Oeveren W, Struck J, Czerwiec FS, Oberdhan D, Krasa HB, Gansevoort RT. Short-term effects of tolvaptan in individuals with autosomal dominant polycystic kidney disease at various levels of kidney function. Am J Kidney Dis 2015;65:833–41.CrossRefPubMed

32.

Mrug M, Zhou J, Woo Y, Cui X, Szalai AJ, Novak J, Churchill GA, Guay-Woodford LM. Overexpression of innate immune response genes in a model of recessive polycystic kidney disease. Kidney Int. 2008;73:63–76.CrossRefPubMed

33.

Norman J. Fibrosis and progression of autosomal dominant polycystic kidney disease (ADPKD). Biochim Biophys Acta. 2011;1812:1327–36.CrossRefPubMedPubMedCentral

34.

Cao Q, Harris DC, Wang Y. Macrophages in kidney injury, inflammation, and fibrosis. Physiology (Bethesda) 2015;30: 183–94.

35.

Zeier M, Fehrenbach P, Geberth S, Mohring K, Waldherr R, Ritz E. Renal histology in polycystic kidney disease with incipient and advanced renal failure. Kidney Int. 1992;42:1259–65.CrossRefPubMed

36.

Ibrahim S. Increased apoptosis and proliferative capacity are early events in cyst formation in autosomal-dominant, polycystic kidney disease. Sci World J. 2007;7:1757–67.CrossRef

Titel: Semaphorin 7A in circulating regulatory T cells is increased in autosomal-dominant polycystic kidney disease and decreases with tolvaptan treatment
Publikationsdatum: 16.02.2018
Erschienen in: Clinical and Experimental Nephrology / Ausgabe 4/2018
Print ISSN: 1342-1751
Elektronische ISSN: 1437-7799
DOI: https://doi.org/10.1007/s10157-018-1542-x

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

24.04.2024 | DGIM 2024 | Kongressbericht | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Semaphorin 7A in circulating regulatory T cells is increased in autosomal-dominant polycystic kidney disease and decreases with tolvaptan treatment

Abstract

Background

Methods

Results

Conclusions

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin

Springer Medizin

Abstract

Background

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2018

Glucosuria and all-cause mortality among general screening participants

Clinical features in a series of 258 Japanese pediatric patients with thrombotic microangiopathy

Recent advances of animal model of focal segmental glomerulosclerosis

Significance of early detection of acute kidney function worsening among outpatients having CKD using automatic calculation system for the rate of eGFR decline

Plasma lyso-Gb3: a biomarker for monitoring fabry patients during enzyme replacement therapy

Inverse correlation between left ventricular end-diastolic pressure and contrast-induced nephropathy in patients undergoing percutaneous coronary intervention

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin