Timothy W. Meyer

Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension.

Two groups of adult male Munich-Wistar rats and a third group of nondiabetic age-matched and weight-matched normal control rats underwent micropuncture study 1 mo, and morphologic studies 14 mo, after induction of streptozotocin diabetes or sham treatment. All animals were fed standard rat chow. Diabetic rats received daily ultralente insulin to maintain stable moderate hyperglycemia (approximately 350 mg/dl). In addition, one group of diabetic rats was treated with the angiotensin I converting enzyme inhibitor, enalapril, 15 mg/liter of drinking water. Average kidney weight, whole kidney and single-nephron glomerular filtration rate, and glomerular plasma flow rate were elevated to similar values in both groups of diabetic rats, relative to normal control rats. Non-enalapril-treated diabetic rats exhibited significant elevations in mean glomerular capillary hydraulic pressure and transcapillary hydraulic pressure gradient, compared with the other groups studied, and only this group eventually developed marked and progressive albuminuria. Likewise, histological examination of the kidneys at 14 mo disclosed a high incidence of glomerular structural abnormalities only in non-enalapril-treated diabetic rats. These findings indicate that prevention of glomerular capillary hypertension in rats with diabetes mellitus effectively protects against the subsequent development of glomerular structural injury and proteinuria. This protection is afforded despite pronounced hyperglycemia and elevated levels of glucosylated hemoglobin, further supporting our view that hemodynamic rather than metabolic factors predominate in the pathogenesis of diabetic glomerulopathy.

Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass.

Micropuncture and morphologic studies were performed in four groups of male Munich-Wistar rats after removal of the right kidney and segmental infarction of two-thirds of the left kidney. Groups 1 and 3 received no specific therapy. Groups 2 and 4 were treated with the angiotensin I converting enzyme inhibitor, enalapril, 50 mg/liter of which was put in their drinking water. All rats were fed standard chow. Groups 1 and 2 underwent micropuncture study 4 wk after renal ablation. Untreated group 1 rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate (SNGFR) due to high average values for the mean glomerular transcapillary hydraulic pressure difference and glomerular plasma flow rate. In group 2 rats, treatment with enalapril prevented systemic hypertension and maintained the mean glomerular transcapillary hydraulic pressure gradient at near-normal levels without significantly compromising SNGFR and the glomerular capillary plasma flow rate, as compared with untreated group 1 rats. Groups 3 and 4 were studied 8 wk after renal ablation. Untreated group 3 rats demonstrated persistent systemic hypertension, progressive proteinuria, and glomerular structural lesions, including mesangial expansion and segmental sclerosis. In group 4 rats, treatment with enalapril maintained systemic blood pressure at normal levels over the 8-wk period and significantly limited the development of proteinuria and glomerular lesions. These studies suggest that control of glomerular hypertension effectively limits glomerular injury in rats with renal ablation, and further support the view that glomerular hemodynamic changes mediate progressive renal injury when nephron number is reduced.

Converting enzyme inhibitor therapy limits progressive glomerular injury in rats with renal insufficiency

Sustained increases in glomerular capillary pressure and flow accompany systemic hypertension in rats that have undergone extensive ablation of the renal mass. These intrarenal hemodynamic changes are, in turn, associated with the progressive development of proteinuria and glomerular sclerosis, leading ultimately to failure of remnant nephron units. The efficacy of antihypertensive therapy with enalapril was evaluated in this animal model of chronic renal insufficiency. A dose of enalapril sufficient to prevent systemic hypertension normalized the glomerular capillary pressure without reducing the glomerular filtration rate in the remnant kidney. Maintenance of normal capillary pressure markedly reduced the development of proteinuria and sclerotic lesions in remnant glomeruli. These results suggest that antihypertensive therapy directed at reducing the glomerular capillary pressure could retard the progressive loss of renal function in patients whose functional renal mass has been reduced by disease.

Dietary Protein Intake and Progressive Glomerular Sclerosis: The Role of Capillary Hypertension and Hyperperfusion in the Progression of Renal Disease

Unrestricted intake of protein-rich foods is accompanied by sustained increases in glomerular capillary pressures and flows. Intrarenal hypertension and hyperperfusion associated with protein intake may eventually cause glomerular sclerosis and account for decreased renal function seen with aging. Further elevation of glomerular capillary pressures and flows contributes to progressive glomerular destruction and eventual loss of renal function when nephron number has been reduced by renal disease. Progressive loss of renal function may be retarded by restriction of protein intake. Protein restriction appears to preserve renal function by limiting intrarenal capillary hypertension and hyperperfusion.

Mechanisms of age-associated glomerular sclerosis

Publisher Summary This chapter discusses the mechanisms of age-associated glomerular sclerosis. Attempts to elucidate the mechanisms responsible for age-related glomerular sclerosis have led to the identification of a number of factors that can be shown to modify the process in experimental animals. Of these, dietary manipulations have been the most dramatic and the most extensively studied. The importance of nutrition in the aging process demonstrated that the restriction of food intake increases the lifespan of laboratory rats. The reduction of dietary protein content delays the development of age-related proteinuria and glomerular sclerosis even when total caloric intake is not restricted. Although the most complete protection of the kidney is afforded by restricting protein intake to levels low enough to limit body growth, significant protection is also afforded by reducing protein intake to a level that does not impair growth. The protein-rich diet characteristic of modern Western society might itself induce chronic renal hyperfiltration and hyperperfusion, and thereby contribute to the functional and structural deterioration of the aging kidney. According to this hypothesis, the excessive glomerular pressures and flows necessary to meet the demands of a multiple meal per day, protein-rich diet may contribute to eventual glomerular sclerosis. By itself, age-related glomerular sclerosis poses no threat to well-being. If, however, intrinsic renal disease or surgical loss of renal tissue adds to the glomerular burden imposed by ad libitum feeding, the course of glomerular sclerosis may be hastened appreciably.