No abstract

The relationships of renal and glomerular hypertrophies to development of hyperfiltration and proteinuria early in streptozotocin-induced diabetes were explored. Control, diabetic, phlorizin-treated controls, and diabetic male Fischer rats were used. Phlorizin (an Na+-glucose cotransport inhibitor) was given at a dose sufficient to normalize blood glucose. Inulin clearance (Cinulin) and protein excretion rate (PER) were measured. For morphometry, kidney sections were stained with periodic acid Schiff. At one week, diabetes PER increased 2.8-folds (P < .001), Cinulin increased 80% (P < .01). Kidney wet and dry weights increased 10%–12% (P < .05), and glomerular tuft area increased 9.3% (P < .001). Phlorizin prevented proteinuria, hyperfiltration, and kidney hypertrophy, but not glomerular hypertrophy. Thus, hyperfiltration, proteinuria, and whole kidney hypertrophy were related to hyperglycemia but not to glomerular growth. Diabetic glomerular hypertrophy constitutes an early event in the progression of glomerular pathology which occurs in the absence of mesangial expansion and persists even after changes in protein excretion and GFR are reversed through glycemic control.

Anthropometric (height, weight, and skinfolds), biochemical (serum proteins, albumin, and cholesterol), metabolic (nitrogen balance and creatinine excretion), hematological (plasma volume, hemoglobin, hematocrit, bone marrow hemosiderin, percent transferrin saturation, vitamin B12, and folic acid) variables and body water compartments (total and extracellular) have been measured in 49 adult male subjects who exhibited a wide range of nutritional states from normal to severely undernourished. Changes in body composition associated with moderate degrees of nutritional compromise were related principally to decreases in body cell mass (-15%). Body fat was normal. With severe nutritional involvement, both fat depots (-29%) and body cell mass (-29%) were significantly diminished. Muscle cell mass was more affected than other cells in the body (-41%). These data could indicate that in the group with moderate compromise, energy reserves (and hence energy balance) were maintained but dietary protein deficiencies were not compensated for. Both calorie and protein deficiencies were evident in the subjects with severe undernutrition. Multiple regression equations (r greater than 0.8) were developed that allow prediction of muscle cell mass, fat-free weight, and body cell mass from simple anthropometry and serum albumin levels. Decreases in serum albumin concentration were best related to deficits in muscle mass (r = 0.77).

Despite similar molecular structures, the growth-related sodium/phosphate cotransporter NaPiIIc is regulated differently than the main NaPiIIa phosphate transporter. Using two-hybrid systems and immunoprecipitation, we identified several proteins that interact with NaPiIIc that might account for this differential regulation. NaPiIIc interacted with the PDZ domain-containing sodium-hydrogen exchange-regulating factor (NHERF) 1 and NHERF3 through novel binding motifs in its C terminus. NaPiIIc from brush-border membranes coprecipitated with both NHERF1 and NHERF3, with more NHERF3 co-precipitated in rats fed a low-phosphorus diet. NaPiIIc colocalizes with both NHERF1 and NHERF3 in brush-border membranes of rats fed either a low- or high-phosphorus diet. When mouse NaPiIIc was transfected into opossum kidney cells, it was localized mainly in apical microvilli and the trans-Golgi. Both confocal and total internal reflection microscopy show that NaPiIIc colocalizes with NHERF1 and NHERF3 in the apical microvilli, and this was not altered by truncation of the last three amino acids of NaPiIIc. Interactions of NaPiIIc with NHERF1 and NHERF3 were modulated by the membrane-associated 17 kDa protein (MAP17) similarly to NaPiIIa, but only the MAP17-NaPiIIc-NHERF3 complexes were internalized to the trans-Golgi. Our study shows that NaPiIIc interacts with a limited number of PDZ domain proteins, and the mechanisms and consequences of such interactions differ from those of NaPiIIa.