Mechanisms in nephrosclerosis and hypertension-beyond hemodynamics.

These studies support that global glomerulosclerosis is a key lesion in human hypertensive nephrosclerosis, and cannot be simply explained by worse vascular sclerosis caused by higher blood pressure. Possible pathogenetic mechanisms include genetic susceptibility, accelerated aging and a primary microvascular disease. The potential importance of the renin angiotensin system in glomerular sclerosis is underscored by the effectiveness of therapies that aim to inhibit its manifold actions, including induction of plasminogen activator inhibitor-1 (PAI-1). Further, regression of existing glomerulosclerosis, including age-related renal and vascular sclerosis, can be achieved in various experimental settings by high dose angiotensin inhibiton, and is linked to inhibition of PAI-1. Ongoing studies will establish which of these provocative findings from animal models are relevant to human diseases, and may lead to optimal therapies to forestall progression and perhaps even induce regression of sclerosis.