PAPP-A in normal human mesangial cells: effect of inflammation and factors related to diabetic nephropathy

What is it about?

Insulin like growth factors (IGFs) are implicated in the development of diabetic nephropathy (DN) and have been shown to increase proliferation and extracellular matrix production in mesangial cells. The IGF system is complex and is composed of ligands, receptors, six binding proteins (IGF BPs) and a novel zinc metalloproteinase, pregnancy associated plasma protein (PAPP)-A. PAPP-A increases the local bioavailability of IGF through the cleavage of IGF BP-4. Mesangial expansion is a major component of DN, and PAPP-A has been shown to be increased in the glomeruli of patients with DN. Therefore, we determined the expression of PAPP-A and components of the IGF system in normal human mesangial cells (HMCs) and their regulation by factors known to be involved in DN. Under basal conditions, HMCs expressed PAPP-A, IGF-I receptor and all six IGF BPs. Interleukin (IL)-1β was the most potent stimulus for PAPP-A expression (5-fold) followed by tumor necrosis factor (TNF)-α (2.5-fold). This PAPP-A was secreted, cell-associated and proteolytically active. IL-1β also increased IGF BP-1expression (3-fold) with either reduction or no effect on other IGF BPs. Generally, TNF- α treatment decreased IGF BP expression. No treatment effect on PAPP-A or IGF BPs was seen with IL-6, IGFs, advanced glycation end products or prolonged hyperglycemia. In addition, stimulation of HMCs with IGF-I alone or IGF-I complexed to wild type, but not protease-resistant, IGF BP-4 led to increased [3H]-thymidine incorporation. In conclusion, these novel findings of PAPP-A and its regulation by pro-inflammatory cytokines, as well as the comprehensive analysis of the IGF system regulation in HMCs, suggest a mechanism by which inflammatory states such as DN can impact IGF activity in the kidney.

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