Michael P. O'Donnell

Lovastatin but not enalapril reduces glomerular injury in Dahl salt-sensitive rats.

Dahl salt-sensitive (S) rats fed a high salt diet develop hypertension, hyperlipidemia, and progressive renal disease. Previous studies have suggested that lipids may be important in the pathogenesis of glomerulosclerosis in Dahl S rats. To investigate this possibility, Dahl S rats fed 4% NaCl chow were treated chronically with the cholesterol synthesis inhibitor lovastatin. After 22 weeks, lovastatin-treated rats had a 38% reduction in serum cholesterol, a 76% reduction in urine albumin excretion, and one-sixth the incidence of focal glomerulosclerosis compared with vehicle-treated control rats. Blood pressure in lovastatin-treated rats was significantly (p < 0.05) lower than that in vehicle-treated rats both early in the study (4 weeks of treatment) and at the end of the protocol. Lovastatin had no effect on glomerular filtration rate or glomerular ultrafiltration dynamics. The efficacy of angiotensin converting enzyme inhibitors in attenuating proteinuria and experimental glomerular disease may be dependent on sodium intake. Thus, we also investigated the effects of long-term enalapril treatment on glomerular injury in Dahl S rats fed high salt chow. Enalapril treatment (50 or 200 mg/l drinking water) significantly lowered blood pressure in Dahl S rats, but did not significantly affect albuminuria or glomerulosclerosis. Enalapril also had no effect on glomerular hemodynamics. These results suggest that lipids may be important in the development of both glomerular disease and hypertension in Dahl S rats and that angiotensin converting enzyme inhibition may not affect the course of renal disease in a setting of high salt intake.

Effects of Nephron Loss on Glomerular Hemodynamics and Morphology in Diabetic Rats

Loss of renal mass in rats with experimental diabetes mellitus leads to exaggerated hypertrophy of remaining nephrons and accelerated diabetic glomerulopathy. To examine factors responsible for glomerular injury in this setting, rats with preexisting diabetes were subjected to unilateral nephrectomy. Micropuncture studies and evaluation of glomerular morphology were performed 2–3 mo later. Nephrectomized diabetic rats demonstrated significant increases in kidney weight, superficial nephron glomerular filtration rate, and superficial nephron plasma flow compared with two-kidney diabetic rats and nephrectomized nondiabetic controls. Glomerular capillary hydraulic pressure was comparable in two-kidney and nephrectomized diabetic rats and was significantly reduced compared with nephrectomized nondiabetic controls. Nephrectomized diabetic rats demonstrated significant albuminuria, mesangial matrix expansion, and focal glomerulosclerosis, whereas two-kidney diabetic rats and nephrectomized nondiabetic controls showed only minimal alterations in glomerular morphology. It is concluded that diabetic rats can undergo glomerular functional compensation in response to nephron loss. Moreover, accelerated glomerular injury caused by nephron loss in diabetic rats could not be attributed to increased glomerular capillary pressure.

Renal tubulointerstitial fibrosis. New thoughts on its development and progression.

PREVIEW Tubulointerstitial fibrosis, characterized by accumulation of extracellular matrix proteins, is a morphologic hallmark of chronic renal disease as well as a component of normal aging in the kidney and of chronic allograft nephropathy. In this article, the author describes patterns that have recently been proposed to explain the pathogenesis of tubulointerstitial injury. In addition, he discusses available and experimental pharmacologic interventions that may ameliorate renal fibrosis.

Inhibition of human mononuclear cell proliferation, interleukin synthesis, mRNA for IL-2, IL-6, and leukotriene B4 synthesis by a lipoxygenase inhibitor

Human peripheral blood mononuclear cells (PBMCs) were cultured in vitro with various stimuli and in the presence or absence of a 5‐lipoxygenase (5‐LO) inhibitor, A‐63162, to measure its effects on PBMC proliferation, interleukin‐2 receptor (IL‐2R) expression, interleukin‐2 (IL‐2) synthesis, interleukin‐6 (IL‐6) synthesis, and accumulation of messenger RNA for IL‐2 or IL‐6. A‐63162 inhibited PBMC proliferation stimulated by phytohemagglutinin (PHA) and phorbol myristate acetate (PMA) plus A23187, IL‐2 receptor expression stimulated by PHA, and IL‐2 or IL‐6 synthesis induced by PHA plus PMA or PMA plus A23187. At the same concentration, A‐63162 inhibited accumulation of mRNA for IL‐2 or IL‐6 and also inhibited leukotriene B4 (LTB.,) synthesis. Our data indicate that the 5‐LO inhibitor A‐63162 has immunosuppressive activity that may be due to inhibition of LTB4 production or to direct inhibitory actions of A‐63162 on IL‐2 and IL‐6 synthesis.

The obese Zucker rat model of glomerular injury in type II diabetes.

Diabetic nephropathy is the most common cause of renal failure in the United States. 1 Although the incidence of nephropathy is higher in Type I diabetes, at least one third of diabetics who develop end-stage renal disease have Type II diabetes. 2 In both Type I and Type II diabetes, the pathogenesis of renal failure is poorly understood. Several studies have been performed using insulin-supplemented, moderately severe hyperglycemic rats made diabetic with alloxan or streptozotocin. The results of investigations using this model have suggested that increased glomerular capil lary pressure and plasma flow may cause glomerular injury in insulin-dependent diabetes. 3 However, these insulin-dependent rat models develop minimal glomerular injury and have not been shown to progress to end-stage renal disease. Thus, the role of altered glomerular hemodynamic function in the pathogenesis of diabetic glomerulosclerosis is still unclear. Even less clear, however, is the pathogenesis of glomerular injury in patients with Type II diabetes, which is often characterized by a genetic predisposition, obesity, hypertension, peripheral insulin resistance, mild hyperglycemia, and hyperlipidemia. 4,5 There have been few investigations of renal disease in animal models of Type II diabetes, although several features of Type II diabetes have been induced in rats fed high sucrose diets. 6 Glomerulosclerosis in this model was associated with glucose intolerance and hypercholesterolemia. 6 In contrast, glomerular injury could not be attributed to hypertension, and hyperglycemia per se did not correlate with focal glomerulosclerosis (FGS). 6 However, which of these factors may be responsible for the glomerular injury in this model, or in patients with Type II diabetes, is unknown. The obese Zucker rat has been used to study endocrinologic and metabolic disturbances characteristic of Type II diabetes. Obese Zucker rats spontaneously develop mild hyperglycemia, elevated plasma insulin levels, and peripheral insulin resistanceJ ,8 Obesity in theZucker rat is an autosomal recessive trait. ~ Like obese humans with Type II diabetes, obese Zucker rats also develop hyperlipidemia and mild hypertension. 8,9 Lean littermates, on the other hand, appear to be normal in all respects. Thus, obese Zucker rats provide an opportunity to investigate the effects of Type II diabetes on renal structure and function, while normal, lean littermates can be used as genetically matched controls.