Pathogenesis of diabetic glomerulopathy: hemodynamic considerations

Abstract

Early stages of diabetes mellitus are characterized by glomerular hyperfiltration in humans and experimental animals. In diabetic rats, single nephron hyperfiltration results from elevations in the glomerular capillary plasma flow rate and hydraulic pressure, which are in turn associated with progressive albuminuria and morphologic injury. Interventions that ameliorate these hemodynamic adaptations afford protection against structural injury. Dietary protein restriction, which lowers glomerular filtration, perfusion, and hydraulic pressure, retards glomerular injury and limits capillary basement membrane thickening in both the glomerular and retinal circulatory beds. Alternatively, selective control of glomerular capillary hypertension using angiotensin I converting enzyme inhibitor therapy limits glomerular injury in this model as well. Each of these interventions is effective even in the absence of improved metabolic control, implying that hemodynamic factors per se are important in this pathogenic process. The pathophysiologic mechanisms of diabetic hyperfiltration remain incompletely elucidated. Recent studies invoke a potential role for atrial natriuretic peptide (ANP). Strict metabolic control abolishes the elevations of glomerular filtration rate and of plasma ANP levels in moderately hyperglycemic diabetic rats. Moreover, infusion of a specific ANP antibody reverses hyperfiltration in diabetic rats. Thus, hyperglycemia-induced chronic volume expansion may trigger ANP release, which in turn contributes to diabetic hyperfiltration. Hemodynamic factors may play an important role in the pathogenesis of extrarenal microangiopathy as well. Elevated peripheral capillary blood flows and/or hydraulic pressure may be found in many peripheral capillaries, in association with thickening of the capillary basement membrane. Dietary protein restriction, which lowers blood flow to many organs, limits retinal as well as glomerular basement membrane thickening in diabetic rats, suggesting that hemodynamically mediated structural injury is a diffuse phenomenon in the diabetic state.