Advanced glycation end products decrease mesangial cell MMP-7: A role in matrix accumulation in diabetic nephropathy?

Abstract

Increased extracellular matrix material is a pathological hallmark of diabetic nephropathy. In addition to collagens, a variety of non-collagenous glycoproteins such as fibronectin also accumulate in the kidney of diabetics. The effect of diabetes on degradative pathways, in particular those involving non-collagenous proteins, are relatively unexplored. In this study, we determined the expression of the major matrix metalloproteinase (MMP) responsible for degrading the non-collagenous matrix glycoprotein fibronectin. Furthermore, the modulation of these MMPs by advanced glycation end products (AGE), a key factor in the diabetic milieu, was explored. Exposure of mesangial cells to AGEs led to a significant reduction in MMP-7, but not MMP-3 or -10. MMP-7 expression was normalized by both aminoguanidine, an inhibitor of glycation product formation, or by a neutralizing anti-transforming growth factor-b (TGF-b) antibody. In streptozotocin-induced diabetic rats, the diminution in MMP-7 expression and excessive fibronectin accumulation were attenuated by aminoguanidine. Humans with type 2 diabetes and nephropathy displayed similar alterations in MMP-7 to their rodent counterparts. Our findings suggest that diminished expression of the glycoprotein-degrading enzyme, MMP-7, may play a role in fibronectin accumulation in the diabetic kidney in response to AGEs and/or TGF-b.

Diabetes-induced peroxynitrite impairs the balance of pro-nerve growth factor and nerve growth factor, and causes neurovascular injury

“…Our results showed diminished expression and activity of MMP-7 in diabetic retinas or in high glucosetreated Müller cells that were restored by FeTPPs or atorvastatin treatment. Supporting this, previous studies demonstrated diminished expression and activity of MMP-7 in streptozotocin-induced diabetic rats [31] and in vitro models in response to hyperglycaemia [32], or oxidative stress via oxidation of active sites of MMP-7 [33]. Moreover, the activity of MMP-7 in aqueous humour samples from PDR patients showed a 50% reduction of MMP-7 activity.…”

Cardiac Protection by Basic Fibroblast Growth Factor from Ischemia/Reperfusion-Induced Injury in Diabetic Rats

“…It is known that antioxidant and angiogenic action of FGF are mediated by signaling pathways that involves in several other kinases, such as Akt, extracellular signal-regulated kinase (Erk1/2), and vascular endothelial growth factor (VEGF). [13][14][15][16]45) As mentioned above, diabetes impairs several antioxidants and growth factors, [17][18][19][20][21] administration of single exogenous rhbFGF alone is unable to overcome all these defectives, and consequently offered a slightly less protection in diabetic rats as compared to that in non-diabetic rats. Therefore, combination of bFGF with other growth factors may be a potential approach to optimize the protective effect of bFGF against I/R-induced cardiac injury 46) even under diabetic conditions, which will be warranty in the future studies.…”

“…[13][14][15][16] For instance, diabetes inhibited the expression, and also induced glycosylation of several growth factors, including endogenous FGF. [17][18][19][20][21] Decreased serum levels of bFGF with other growth factors were found to increase cardiovascular events (including infarction, revascularization, stroke and peripheral vascular disease) in diabetic patients. 22) Supplementation of exogenous FGFs attenuated diabetes-caused neuronal and gastric tissue damage.…”

Evaluation of role of doxycycline (a matrix metalloproteinase inhibitor) on renal functions in patients of diabetic nephropathy

“…25 A study by McLennan postulates that MMP-7, responsible for degradation of noncollagenous glycoproteins, is reduced in diabetic kidney and that advanced glycation end products (AGEs), acting via TGF-b-dependent mechanisms, contribute to this process. 26 The present study showed that the level of proteinuria in patients with overt DN can be decreased with a low-dose doxycycline therapy. The delayed response seen after 3 months and not immediately after 1 month may be due to altered expression of MMPs and degradation of ECM proteins in the presence of the drug.…”