title: The Role of Congestion in Cardiorenal Syndrome Type 2: New Pathophysiological Insights into an Experimental Model of Heart Failure.
abstract: BACKGROUND
  In cardiorenal syndrome type 2 (CRS2), the role of systemic congestion in heart failure (HF) is still obscure. We studied a model of CRS2 [monocrotaline (MCT)-treated rats] secondary to pulmonary hypertension and right ventricular (RV) failure in order to evaluate the contribution of prevalent congestion to the development of kidney injury.
  
  
  METHODS
  Ten animals were treated with MCT for 4 weeks until they developed HF. Eleven animals were taken as controls. Signs of hypertrophy and dilatation of the right ventricle demonstrated the occurrence of HF. Brain natriuretic peptide (BNP), serum creatinine (sCreatinine), both kidney and heart neutrophil gelatinase-associated lipocalin (NGAL), matrix metallopeptidase 9 (MMP9), serum cytokines as well as kidney and heart cell death, as assessed by TUNEL, were studied.
  
  
  RESULTS
  Rats with HF showed higher BNP levels [chronic HF (CHF) 4.8 ± 0.5 ng/ml; controls 1.5 ± 0.2 ng/ml; p < 0.0001], marked RV hypertrophy and dilatation (RV mass/RV volume: CHF 1.46 ± 0.31, controls 2.41 ± 0.81; p < 0.01) as well as pleural and peritoneal effusions. A significant increase in proinflammatory cytokines and sCreatinine was observed (CHF 3.06 ± 1.3 pg/ml vs. controls 0.54 ± 0.23 pg/ml; p = 0.04). Serum (CHF 562.7 ± 93.34 ng/ml vs. controls 245.3 ± 58.19 ng/ml; p = 0.02) as well as renal and heart tissue NGAL levels [CHF 70,680 ± 4,337 arbitrary units (AU) vs. controls 32,120 ± 4,961 AU; p = 0.001] rose significantly, and they were found to be complexed with MMP9 in CHF rats. A higher number of kidney TUNEL-positive tubular cells was also detected (CHF 114.01 ± 45.93 vs. controls 16.36 ± 11.60 cells/mm(2); p = 0.0004).
  
  
  CONCLUSIONS
  In this model of CHF with prevalent congestion, kidney injury is characterized by tubular damage and systemic inflammation. The upregulated NGAL complexed with MMP9 perpetuates the vicious circle of kidney/heart damage by enhancing the enzymatic activity of MMP9 with extracellular matrix degradation, worsening heart remodeling.
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Vicenza, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Angelini
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Vicenza, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Castellani
authors.affiliation: Department of Nephrology, International Renal Research Institute Vicenza (IRRIV), Vicenza, Italy.
authors.forename: Grazia Maria
authors.initials: GM
authors.lastname: Virzì
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Vicenza, Italy.
authors.forename: Marny
authors.initials: M
authors.lastname: Fedrigo
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Vicenza, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Thiene
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Vicenza, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Valente
authors.affiliation: Department of Nephrology, International Renal Research Institute Vicenza (IRRIV), Vicenza, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ronco
authors.affiliation: Internal Medicine Unit, Sant'Antonio Hospital Padua, Padua, Vicenza, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Vescovo
keywords: Cardiorenal syndromes; Cytokines; Heart failure; Kidney injury; Matrix metallopeptidase 9; Neutrophil gelatinase-associated lipocalin