Table 2.

Observations and proposed mechanisms of increased capillary bm thickening with appliations to the myocardial, intima, islet, neuronal unit, Endothelial, renal, retinal and skeletal capillary basement membranes (Increased synthesis and decreased degradation tips the balance to accumulation)

Observations	Proposed mechanisms
Glucotoxicity: IGT postprandial, IFG, and overt T2DM	Protein Kinase C (PKC) activation. Altered integrin expression of podocyte and pericyte: (podocyte-pericyte loss)
Increased Synthesis Of: Type Iv Collagen	TGF beta, VEGF, and possibly PDGF beta 1. All associated with PKC activation and induction of growth hormones – factors from glucotoxicity and → ROS.
Increased Maintenance of: type IV Collagen AGE cross-linking of type IV collagen. AGE – RAGE connection.	Increased resistance to protease (MMP) degradation, allowing type IV collagen to accumulate.
Decreased Degradation.	Decreased MMP-2 MMP-3
Decreased Degradation.	Increased expression of TIMP-2
Increased ROS. In general, ROS promotes ECM fibrosis under the influence of chronic injurious stimuli and is associated with the chronic inflammatory state.	ROS increases all aspects of type IV accumulation: Glucotoxicity → PKC activation, AGE cross-linking activation, Decreased eNOS and eNO activity resulting in increased MMP activation.*

*Comment: It seems whenever there is robust MMP activation the result is robust newly synthesized collagen, which is more susceptible to ROS oxidation and accumulation. In general, it is more difficult to degrade newly synthesized – oxidized collagen than non-oxidized collagen. Other observations include an association of decreased eNO and increased activation of MMPs and in a like manner when eNO is normal or elevated MMP activity is suppressed. This comment points to the importance of a healthy eNOS and eNO generating endothelium in order for the ECM to maintain homeostasis.

Endothelial nitric oxide synthase (eNOS) – Endothelial nitric oxide (eNO)