IMBALANCE IN BONE MORPHOGENIC PROTEINS 2 AND 7 IS ASSOCIATED WITH HYPERTENSION AND ARTERIAL STIFFNESS IN CHRONIC KIDNEY DISEASE

Abstract

Objective: Patients with chronic kidney disease (CKD) exhibit an elevated cardiovascular risk from the early stages (I-III) with an exponentially increasing risk of cardiovascular death as kidney function worsens. The hypothesis of this study is that there is a imbalance in bone morphogenetic proteins BMP-2 (procalcifying) and BMP-7 (renoprotective) at early CKD stages associated with the development of hypertension, vascular stiffness and progressive kidney damage. Design and method: BMP-2 and BMP-7 levels were determined by ELISA in samples of CKD patients (stages I-III; n = 95) and of Munich Wistar Frömter (MWF) rats (22 weeks old; n = 6), a genetic model with spontaneous nondiabetic CKD, compared to age-matched Wistar rats. Results: Plasma BMP-2 levels were significantly higher in stage III CKD patients compared to controls. BMP-7 was, however, significantly lower at any stage of CKD compared to the control group with a significant further reduction in stage III patients. MWF rats presented significantly higher BMP-2 plasma levels compared to Wistar rats, whereas BMP-7 level was lower. The MWF strain showed an elevation of both systolic (SBP) and diastolic blood pressure (DBP), as well as pulse wave velocity (PWV) compared to the Wistar group. A positive correlation was observed between the BMP-2/BMP-7 ratio and SBP, DBP, and PWV, respectively. Plasma 25-OH cholecalciferol concentration was lower in MWF showing a negative correlation with the BMP-2/BMP-7 plasma ratio. Urinary albumin excretion (UAE), tubular damage markers, Kim-1 and Ngal, as well as renal BMP-2 were significantly higher in the MWF group compared to Wistar, whereas renal BMP-7 expression was significantly lower. A positive correlation was detected between the BMP-2/BMP-7 ratio and both the UAE and plasma creatinine level. Periaortic and mesenteric perivascular adipose tissue (PVAT) from MWF rats showed an altered expression of BMP-2, BMP-7, profibrotic and calcification markers. Conclusions: Our data show an imbalance in plasma, kidney and PVAT-derived BMP-2 and BMP-7 levels associated with hypertension and arterial stiffness. This might reflect a profibrotic/pro-calcifying propensity related with progressive CKD.