Markers of Vascular Calcification in Diabetic Nephropathy in Patients With Diabetic Nephropathy

Osteopontin (OPN) is one of integrin-binding N-linked glycoproteins, which is produced by activated mononuclear cells and is linked to increasing evidence about the role of OPN in vascular calcification[1].

Recent clinical studies have shown that vascular calcification is a pathological process leading to mechanical rigidity and stiffness of vascular wall, endothelial dysfunction, development and accelerating atherosclerosis even in the absence of established cardiovascular (CV) disease . Ectopic calcification is explained by several mutually counteracting molecular mechanisms, i.e. oxidative stress, microvascular inflammation, immune cell-to-cell cooperation, accumulation of lipids and extracellular proteins, vascular reparative systems, and metabolic disorders All these processes are under tight regulation of vitamin D, parathyroid hormone-related peptides (fibroblast growth factor, transcription factor Sox2, beta-catenin, etc) and matricellular proteins such as OPN. [2].

OPN was found to have relation with vascular calcification, atherosclerosis, and CV disease associated with severe vascular remodelling including hypertension, chronic kidney disease, diabetes mellitus . In this context, OPN is a promising biomarker of vascular remodelling closely related to inflammation intensity, glucose level and pro-thrombotic state with promising predictive value for CV events [3].

It is a matricellular protein that was first identified in 1995 by Heingard et al. as sialoprotein derived from bovine bone matrix . During the last decade a number of studies analysed the role of OPN in the pathogenesis of diabetic nephropathy. This proposed association needs confirmation and detailed description by further research [4].

At first, OPN has been reported to be highly expressed in the tubular epithelium of the renal cortex and in glomeruli in rat and mouse models of diabetic nephropathy [5]. This was associated with extensive macrophage accumulation in the kidney interstitium indicating that OPN upregulation and macrophage recruitment may play a role in the tubulo-interstitial injury in diabetic nephropathy [6]. Consistently, OPN/mice are protected from diabetes-induced albuminuria and renal damage, possibly by modulating podocyte signaling and motility [7]. In humans, plasma OPN levels are independently associated with presence and severity of diabetic nephropathy [8] Compelling evidence in the literature provides interesting clues about a link between the rennin-angiotensin system (RAS) and OPN in diabetic kidney disease. Diabetes-induced OPN expression and macrophage accumulation in the kidney interstitium of diabetic rats are significantly ameliorated after treatment with the long acting ACE inhibitor [9]. Showing that treatment with ramipril for nine month improves creatinine clearance rate and decreases urinary protein excretion, systolic blood pressure, development of glomerulosclerosis, tubulo-interstitial fibrosis and inflammatory cell infiltration in a diabetics. Of note, all these effects of ACE inhibition were associated with markedly suppressed OPN expression, suggesting that blockade of the RAS by ramipril may confer renoprotection by decreasing OPN secretion in diabetic nephropathy [10]. Liver X receptors (LXRs) have been identified as important lipid-dependent regulators of glucose metabolism and immune functions in leukocytes [11]. Synthetic LXR ligands can inhibit cytokine-induced OPN expression in macrophages [12]. Tachibana and colleges recently observed decreased urinary albumin excretion and substantially attenuated macrophage infiltration, mesangial matrix accumulation and interstitial fibrosis in streptozotocin-induced diabetics following administration of the LXR agonist T0901317. Notably, this was paralleled by diminished OPN expression in the kidney cortex indicating that inhibition of renal OPN by LXR activation may provide a potential therapeutical approach for diabetic nephropathy [13].

Osteopontin (OPN) is a multifunctional protein expressed by several different cell types, although the bone is known to be a major source [14].The exact excretion pathway of OPN from the body is not known. OPN is involved in a number of physiological and pathological conditions, including (1), urinary stones (2), wound healing (3), chronic inflammatory and autoimmune diseases (4), obesity-related chronic inflammation, and insulin resistance. However, OPN was originally found in bone and shown to regulate the formation and calcification of bone tissue. [15].

Notably, OPN has also been linked to vascular remodelling and calcification, especially in diabetic arteries, and has been shown to associate with diabetic retinopathy and nephropathy in patients with type 2 diabetes (T2D), as well as cardiovascular disease (CVD) events in diabetic subjects with history of long standing diabetes. [16]