Imbalance in Bone Morphogenic Proteins 2 and 7 Is Associated with Renal and Cardiovascular Damage in Chronic Kidney Disease

Abstract

Arterial stiffness is a major vascular complication of chronic kidney disease (CKD). The development of renal damage, hypertension, and increased pulse wave velocity (PWV) in CKD might be associated with an imbalance in bone morphogenetic proteins (BMP)-2 and BMP-7. Plasma BMP-2 and BMP-7 were determined by ELISA in CKD patients (stages I–III; n = 95) and Munich Wistar Frömter (MWF) rats. Age-matched Wistar rats were used as a control. The expression of BMP-2, BMP-7, and profibrotic and calcification factors was determined in kidney and perivascular adipose tissues (PVAT). BMP-2 was higher in stage III CKD patients compared to control subjects. BMP-7 was lower at any CKD stage compared to controls, with a significant further reduction in stage III patients. A similar imbalance was observed in MWF rats together with the increase in systolic (SBP) and diastolic blood pressure (DBP), or pulse wave velocity (PWV). MWF exhibited elevated urinary albumin excretion (UAE) and renal expression of BMP-2 or kidney damage markers, Kim-1 and Ngal, whereas renal BMP-7 was significantly lower than in Wistar rats. SBP, DBP, PWV, UAE, and plasma creatinine positively correlated with the plasma BMP-2/BMP-7 ratio. Periaortic and mesenteric PVAT from MWF rats showed an increased expression of BMP-2 and profibrotic and calcification markers compared to Wistar rats, together with a reduced BMP-7 expression. BMP-2 and BMP-7 imbalance in plasma, kidney, and PVATs is associated with vascular damage, suggesting a profibrotic/pro-calcifying propensity associated with progressive CKD. Thus, their combined analysis stratified by CKD stages might be of clinical interest to provide information about the degree of renal and vascular damage in CKD.

Upregulation in Inflammation and Collagen Expression in Perirenal but Not in Mesenteric Adipose Tissue from Diabetic Munich Wistar Frömter Rats

“…As described before, the MWF rat model develops progressive kidney injury, mild hypertension, and vascular disease with age, starting with early progressive albuminuria development at 8-weeks of age, followed by endothelial dysfunction, hypertension, arterial stiffness, and increased pulse wave velocity [21][22][23][24][25][26][27][28]. In this study, the high-energy/STZ model was developed at 16 weeks of age, at which kidney and cardiovascular damage is already established before diabetes induction.…”

“…The Munich Wistar Frömter (MWF) rat is a genetic model of spontaneous and progressive non-diabetic albuminuria development [20] that mirrors several features that have been observed in patients with CKD [21,22]. In response to an inherited nephron deficit of 30-50%, this model shows glomerular hyperfiltration and develops progressive albuminuria, kidney injury (glomerulosclerosis and interstitial fibrosis), mild hypertension, and vascular disease with age: albuminuria (8-week-old rats), endothelial dysfunction (12-week-old rats), hypertension (14-week-old rats), arterial stiffness (16-week-old rats), and increased pulse wave velocity (22-week-old rats) [21][22][23][24][25][26][27][28].…”

An Outline on the Advancements in Surgical Management of Osteoporosis-Associated Fractures

“…However, BMP usage has drawbacks. Arterial stiffness, common in chronic kidney disease (CKD), may be linked to an imbalance in BMP-2 and BMP-7, leading to renal damage, hypertension, and increased pulse wave velocity (PWV) in CKD [67]. It is observed that osteoblast-derived BMP2 is involved in bone quality; thus, deficiency of BMP2 affects bone strength [68].…”

Vascular calcification in CKD: New insights into its mechanisms

“…As a pro‐calcification factor, it is known for its role in inducing the osteochondral transdifferentiation of VSMCs. A number of BMPs have been localized at sites of VC and BMP‐2, ‐4, ‐5, ‐6, and ‐9 have a clear osteogenic capacity, nevertheless BMP‐7 has an inhibitory activity (Hruska et al, 2005; Manzano‐Lista et al, 2022). Among them, BMP‐2 is the most extensively investigated in VC.…”