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Increased proinflammatory cytokine production in adipose tissue of obese patients with chronic kidney disease

Erhöhte Expression von proinflammatorischen Zytokinen im Fettgewebe von adipösen Patienten mit chronischer Niereninsuffizienz

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Zusammenfassung

HINTERGRUND: Die Adipositas ist ein Hochrisikofaktor sowohl für die Entwicklung von Gefäßerkrankungen als auch für chronische Niereninsuffizienz (CKD). Ziel dieser Studie ist es, den Einfluss des Fettgewebes auf den Entzündungsstatus bei adipösen Patienten mit CDK zu erfassen. PATIENTEN UND METHODEN: In einer prospektiven Querschnitt-Studie analysierten wir 40 CDK (Stadium 3–4) Patienten mit milder Proteinurie (2,3–3,5 g/Tag): 20 Patienten mit Adipositas (Gruppe 1) und 20 normalgewichtigen Patienten (Gruppe 2) wurde während einer elektiven Abdominaloperation (laparoskopische Cholecystektomie) einmalig Blut abgenommen, sowie Proben des subkutanen und des viszeralen Fettgewebes entnommen. Die Serumkonzentrationen folgender Parameter wurden bestimmt: Asymmetrisches Dimethylarginin (ADMA), Adiponektin (ADPN), C-reaktives Protein (CRP), Interleukin-6-(IL-6), Tumor Nekrose Faktor-α (TNF-α), Pentosidin, Monocyte Chemoattractant Protein-1 (MCP-1). Mit Hilfe von Real-Time-PCR wurde die Expression der Messenger RNA (mRNA) von TNF-α, MCP-1 und der Adiponektin Rezeptoren 1 und 2 sowie des immunkompetenten Zellmarkers CD68 im subkutanen sowie im viszeralen Fettgewebe bestimmt. Das Fettgewebe wurde immunhistochemisch auf CD68 positive Zellen geprüft. Außerdem wurden in beiden Gruppen folgende weitere biochemische Parameter bestimmt: Insulin, HbA1c, Cholesterin, LDL-Cholesterin, und Triglyzeride. ERGEBNISSE: Die Serumkonzentrationen von ADMA, CRP, Pentosidin, Interleukin-6, TNF-α, and MCP-1 waren bei den adipösen CDK-Patienten signifikant höher. Das Adiponektin war signifikant im Vergleich zur Kontrollgruppe erniedrigt. Die subkutane und viszerale mRNA Expression von TNF-α, CD68, Adiponektin Rezeptor-1 and MCP-1 war bei den adipösen CDK Patienten signifikant erhöht. Die mRNA Expressionen waren im viszeralen Fettgewebe signifikant höher als im subkutanen Fettgewebe (p < 0,01 vs. p < 0,05). Die Expressionen der mRNA von Adiponektin, Interleukin-6, und des Adiponektin Rezeptors-2 beider Fettdepots waren nicht unterschiedlich in den beiden Gruppen. Bei den adipösen CDK-Patienten wurde im subkutanen und im viszeralen Fettgewebe eine erhöhte Infiltration mit CD68 positiven immunkompetenten Zellen gefunden. Die Fettstoffwechsel-Parameter waren in der Gruppe 1 gering, aber signifikant (p < 0,02) erhöht. Ausgeprägter waren die Veränderungen in den Triglyzeriden (p < 0,01). Ein ähnlicher Anstieg wurde bei den Insulin und HbA1c Werten der Gruppe 1 beobachtet (p < 0,02). SCHLUSSFOLGERUNGEN: Im Fettgewebe adipöser Patienten mit CKD im Stadium 3–4 wurde eine erhöhte Expression von proinflammatorischen Zytokinen und eine gesteigerte Infiltration mit immunkompetenten Zellen gefunden. Diese hinauf-regulierte Entzündung könnte zur Auslösung eines systemischen proinflammatorischen Zustands bei Patienten mit CDK beitragen und das Fortschreiten der Störung der Nierenfunktion beschleunigen.

Summary

BACKGROUND: Obesity is a known high-risk factor for the development of vascular diseases and chronic kidney disease (CKD). In this study we aimed to elucidate the impact of adipose tissue on the inflammatory state in CDK patients with obesity. PATIENTS AND METHODS: A cohort of 40 patients with CKD (stages 3–4) with mild proteinuria (2.3–3.5 g/day) were analyzed in a prospective cross-sectional study: single blood samples and visceral and subcutaneous samples of adipose tissue were taken from 20 patients with obesity and 20 without obesity (control group) during elective abdominal surgery (laparoscopic cholecystectomy). Serum concentrations of asymmetric dimethylarginine (ADMA), adiponectin, C-reactive protein, interleukin-6, tumor necrosis factor-α, pentosidine and monocyte chemoattractant protein-1 were measured. Messenger RNA expression of tumor necrosis factor-α, monocyte chemoattractant protein-1, adiponectin receptors 1 and 2, and immunocompetent cell marker CD68 was measured in subcutaneous and visceral fat samples using real-time PCR. Adipose tissue was examined immunohistochemically for CD68-positive cells. Other biochemical parameters (insulin, glycated hemoglobin, cholesterol, LDL cholesterol, and triglycerides) were assessed in the two groups of patients at the same time. RESULTS: Serum concentrations of ADMA, C-reactive protein, pentosidine, interleukin-6, tumor necrosis factor-α and monocyte chemoattractant protein-1 were significantly higher in obese CKD patients than in the control group; adiponectin was lower in the obese group. Subcutaneous and visceral mRNA expressions of tumor necrosis factor-α, CD68, adiponectin receptor-1, and monocyte chemoattractant protein-1 were significantly increased in the obese patients, whereas expression of adiponectin, interleukin-6, and adiponectin receptor-2 did not significantly differ between the patient groups. In general, mRNA expressions were higher in visceral than in subcutaneous samples (P < 0.01 vs. P < 0.05). Increased infiltration of subcutaneous and visceral adipose tissue by CD68-positive immunocompetent cells was found in the obese CKD group. With respect to lipid metabolism parameters, a small but significant increase in levels was found in the obese patients (P < 0.02). Changes in triglycerides were more marked in this group (P < 0.01) and a similar increase was noted in insulin and HbA1c levels (P < 0.02). CONCLUSION: Increased expression of proinflammatory cytokines and increased infiltration by immunocompetent cells were found in adipose tissue of obese patients with CKD stages 3–4. This upregulated inflammation may contribute to the induction of a systemic proinflammatory state in patients with CKD and could accelerate the progression of renal dysfunction.

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Authors and Affiliations

  1. IIIrd Medical Faculty, Department of Surgery, Charles University, Prague, Czech Republic

    Vladimír Teplan Jr, František Vyhnánek & Robert Gürlich

  2. Ist Medical Faculty, 3rd Department of Internal Medicine, Prague, Czech Republic

    Martin Haluzík

  3. Medical Faculty, Institute of Clinical Biochemistry and Hematology, Charles University, Pilsen, Czech Republic

    Jaroslav Racek

  4. Ist Medical Faculty, 2nd Department of Internal Medicine, Thomayer Hospital, Charles University, Prague, Czech Republic

    Ivana Vyhnankova

  5. Transplant Center, Department of Nephrology, Institute for Clinical and Experimental Medicine and Institute for Postgraduate Education, Prague, Czech Republic

    Milena Štollová & Vladimír Teplan

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  1. Vladimír Teplan Jr
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  2. František Vyhnánek
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  3. Robert Gürlich
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Teplan, V., Vyhnánek, F., Gürlich, R. et al. Increased proinflammatory cytokine production in adipose tissue of obese patients with chronic kidney disease. Wien Klin Wochenschr 122, 466–473 (2010). https://doi.org/10.1007/s00508-010-1409-y

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