The key role of the transforming growth factor-beta system in the pathogenesis of diabetic nephropathy.

Progressive renal injury in diabetes mellitus leads to major morbidity and mortality. The manifestations of diabetic nephropathy may be a consequence of the actions of certain cytokines and growth factors. Prominent among these is transforming growth factor-beta (TGF-beta) because it promotes renal cell hypertrophy and stimulates extracellular matrix accumulation, the two hallmarks of diabetic renal disease. In cell culture, high ambient glucose increases TGF-beta mRNA and protein in proximal tubular, glomerular epithelial, and mesangial cells. Neutralizing anti-TGF-beta antibodies prevent the hypertrophic and matrix stimulatory effects of high glucose in these cells. In experimental and human diabetes mellitus, several reports describe overexpression of TGF-beta in the glomeruli and tubulointerstitium. We demonstrate that short-term treatment of diabetic mice with neutralizing monoclonal antibodies against TGF-beta significantly reduces kidney weight and glomerular hypertrophy and attenuates the increase in extracellular matrix mRNAs. Long-term treatment of diabetic mice further improves the renal pathology and also ameliorates the functional abnormalities of diabetic nephropathy. Finally, we provide evidence that the renal TGF-beta system is significantly up-regulated in human diabetes. The kidney of a diabetic patient actually elaborates TGF-beta1 protein into the circulation whereas the kidney of a non-diabetic subject extracts TGF-beta1 from the circulation. The data we review here strongly support the hypothesis that elevated production or activity of the TGF-beta system mediates diabetic renal hypertrophy and extracellular matrix expansion.

Leptin stimulates type I collagen production in db/db mesangial cells: glucose uptake and TGF-beta type II receptor expression.

BACKGROUND: Serum leptin levels correlate with fat cell mass and are elevated in patients with massive obesity and type 2 diabetes mellitus, which are strong risk factors for the development of glomerulosclerosis. We have previously shown in cultured glomerular endothelial cells that leptin stimulates cellular proliferation and expression of the prosclerotic cytokine transforming growth factor-beta1 (TGF-beta1). Although the effect of leptin on the hypothalamus to regulate energy homeostasis is well known, the effect of leptin on the kidney, and specifically on the glomerular mesangial cell, is unclear. METHODS: The obese, diabetic db/db mouse, which lacks the functional full-length Ob-Rb leptin receptor, is a suitable model to assess the effects of hyperleptinemia on peripheral tissues that express other receptor isoforms. The effects of leptin on glucose uptake, the TGF-beta system, and type I collagen production were evaluated in db/db mouse mesangial cells in culture. A phosphatidylinositol-3 kinase (PI-3K) inhibitor was used to assess the role of PI-3K in mediating the effects of leptin. RESULTS: A short form of the leptin receptor (Ob-Ra), but not Ob-Rb, was present by reverse transcription-polymerase chain reaction in the kidney and mesangial cells of both nondiabetic db/m and diabetic db/db mice. In db/db mesangial cells, leptin increased 2-deoxy-D-glucose (2DOG) uptake dose dependently and stimulated gene expression of TGF-beta type II receptor (TbetaRII) and alpha1(I) collagen, but not TGF-beta1. Protein production of type I collagen (enzyme-linked immunosorbent assay) was also increased by leptin. Both leptin-stimulated 2DOG uptake and type I collagen production were suppressed by a PI-3K inhibitor, LY294002. Mesangial cells pretreated with leptin exhibited increased responsiveness to exogenous TGF-beta1, as evidenced by a greater production of type I collagen protein in leptin-pretreated cells exposed to low-dose TGF-beta1 (0.5 ng/mL). The addition of both TGF-beta1 (2 ng/mL) and leptin (100 ng/mL) increased type I collagen production more than addition of either TGF-beta1 or leptin alone. CONCLUSIONS: Leptin increases glucose uptake and type I collagen in db/db mesangial cells through a PI-3K-dependent pathway. We postulate that increased leptin levels may transmit a signal through the short-form leptin receptor to up-regulate TbetaRII and activate the intraglomerular TGF-beta system, which may contribute to the glomerulosclerosis of obesity or type 2 diabetes.

The incidence and economic significance of ovine toxoplasmosis in Uruguay.

Antibodies to Toxoplasma gondii were measured before and after pregnancy in a 1:64 dilution of sera with the direct agglutination test in 1613 ewes from 18 farms in eight different counties of Uruguay from 1992 to 1994. The overall seroprevalence increased from 28.7% before mating to 38.5% after lambing in 2.5 years and thus the incidence was 9.8%. Losses due to toxoplasmosis during pregnancy were estimated to be 1.4-3.9% of the total number of ewes investigated, amounting to approximately US$1.4-4.7 million for the whole country.

The incidence and economic significance of ovine toxoplasmosis in Uruguay.

Antibodies to Toxoplasma gondii were measured before and after pregnancy in a 1:64 dilution of sera with the direct agglutination test in 1613 ewes from 18 farms in 8 different counties of Uruguay from 1992 to 1994. The overall seroprevalence increased from 28.7% before mating to 38.5% after lambing in 2.5 yr and thus, the incidence was 9.8%. Losses due to toxoplasmosis during pregnancy were estimated to be 1.4 to 3.9% of the total number of ewes investigated, amounting to approximately US$1.4-4.7 million for the whole country.

Effects of chronic uremia, hemodialysis, and renal transplantation on plasma lipids and lipoproteins in man.

Since quantitative and qualitative alterations in plasma lipoproteins may provide insights into mechanism(s) of altered lipid transport in renal failure, whole plasma triglyceride (TG) and cholesterol (Chol) concentrations and lipoprotein neutral lipids and composition were examined in patients with chronic renal failure (undialyzed and dialyzed) and following successful renal transplantation. Both uremic groups demonstrated increased TG (p less than 0.001) and normal Chol in whole plasma and increased total TG and Chol in the very low-density lipoprotein fraction (VLDL). All hyperlipidemic subjects showed a Type IV phenotype. The percentage triglyceride in VLDL was slightly higher than control in the dialysis patients, and significantly increased in LDL in both undialyzed (p less than 0.001) and dialyzed (p less than 0.005) uremic groups. Transplant patients had significant increases (p less than 0.001) in both TG and Chol in whole plasma, and increased total TG and Chol in both the low-density lipoproteins (LDL) and VLDL fractions. Transplant patients with hyperlipidemia showed a variety of phenotypes and an enrichment of triglyceride in VLDL and LDL. These findings indicate that abnormalities in lipoprotein metabolism in renal failure patients are not appreciably affected by chronic dialysis treatment and continue following successful transplantation. The tendency toward increased VLDL and LDL triglyceride content in these patients resembles the lipoprotein neutral lipid composition found in nonrenal patients with similarly elevated plasma lipids. These alterations could result from primary disturbances in VLDL production and/or removal.