Forebrain expression of c-fos due to active maternal behaviour in lactating rats.

To reveal brain sites simultaneously active during the expression of maternal behaviour in lactating rats, we used immunocytochemical visualization of the nuclear protein product Fos of the immediate-early gene c-fos as a marker of neuronal activity. After a 48 h separation from their litter, day 7 postpartum dams received a 1 h period of physical interaction with pups either capable or incapable of suckling, inaccessible pups in a wire-mesh box, an empty box, or no stimulation. Physical interaction with pups elicited high levels of pronurturant maternal behaviour (retrieval, licking, mouthing), and suckling elicited nursing behaviour as well. Exposure to the box, with or without pups, elicited high levels of investigatory sniffing, self-grooming, and general activity. Distal stimulation from pups did not differentially activate Fos in any of 20 sites, including olfactory-processing structures such as the piriform cortex and medial amygdala. Physical interaction with pups, with or without suckling, elicited higher levels of Fos-immunoreactive nuclei than that of other conditions in numerous sites, including many previously implicated in maternal behaviour (medial preoptic nucleus, nucleus accumbens, lateral septum, lateral habenula, and the bed nucleus of the stria terminalis). Similar group patterns of Fos expression also occurred in sites not previously implicated in maternal behaviour (somatosensory cortex and paraventricular thalamic nucleus). Interaction with nonsuckling pups elicited the highest levels of Fos in the cortical amygdala, whereas suckling did not activate higher Fos than nonsuckling interaction in any site included in this report, including hypothalamic nuclei involved in lactation (paraventricular, supraoptic, and arcuate). There was little or no Fos in cingulate cortex, olfactory tubercle, medial septum, medial habenula, or ventromedial hypothalamus. These data suggest that trigeminal stimuli received by lactating rats during the performance of pronurturant maternal behaviour promote cellular activity resulting in neuronal expression of c-fos in many forebrain sites including the medial preoptic nucleus, several sites connected with it that are part of the mesotelencephalic dopamine system, and in the somatosensory cortex. In contrast, in these forebrain sites suckling does not elicit greater levels of Fos than that seen in nonsuckled rats and distal stimuli from pups are ineffective in increasing Fos levels compared with non-stimulated controls.

Effect of myo-inositol on cell proliferation and collagen transcription and secretion in proximal tubule cells cultured in elevated glucose.

Tubulointerstitial lesions often develop in the kidneys of patients and experimental animals with diabetes mellitus. In an in vitro model of diabetic renal disease, it has been previously demonstrated in this laboratory that elevated glucose levels stimulate procollagen transcription and secretion in proximal tubule cells in culture while inducing cellular hypertrophy and reducing cellular proliferation. Previous experiments in other tissues have suggested that myo-inositol supplementation, probably by reversing a disturbance in cell myo-inositol metabolism related to increased activity of the polyol pathway, reverses the effects of glucose on cell function. We tested the effect of myo-inositol supplementation on proximal tubule cells in culture in the presence of elevated medium glucose level. Incubation in 450 mg/dL of glucose media reduced cell proliferation; 450 mg/dL of glucose plus myo-inositol (800 microM) increased proliferation, returning the value to that seen in cells incubated in 100 mg/dL of glucose. Incubation in 450 mg/dL of glucose media increased type IV and type I procollagen mRNA levels and peptide secretion rates compared with those seen in cells incubated in medium containing 100 mg/dL of glucose. This glucose-induced stimulation of procollagen mRNA levels and procollagen secretion was not observed when the elevated glucose medium was supplemented with 800 microM myo-inositol. On the other hand, myo-inositol supplementation did not prevent the glucose-induced cellular hypertrophy: there was no reduction in the increased leucine incorporation and cellular protein content. Cell incubation in 450 mg/dL of glucose media did not lead to a measurable decrease in total cellular myo-inositol.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of polyol-pathway inhibition and dietary myo-inositol on glomerular hemodynamic function in experimental diabetes mellitus in rats.

Early functional disturbances in nerve, retina, and lens in diabetes mellitus appear to result from a common mechanism involving increased polyol-pathway activity with an associated effect on tissue myo-inositol metabolism. We tested the role of increased polyol-pathway activity in the early glomerular hemodynamic abnormalities in experimental diabetes in rats with dietary myo-inositol supplementation or the administration of sorbinil, an aldose reductase inhibitor. Each maneuver prevented the glomerular hyperfiltration of early streptozocin-induced diabetes and reversed the hyperfiltration of established diabetes of 10 days' duration. We also found that the abnormal response to captopril in diabetic rats was improved by dietary myo-inositol supplementation or sorbinil administration. Although nonhypotensive doses of captopril lowered glomerular filtration rate (GFR) in diabetic rats on a 0.01% myo-inositol diet, GFR increased substantially after captopril infusion in diabetic rats treated with sorbinil or myo-inositol supplementation. These data suggest that normalization of tissue myo-inositol metabolism restores normal responsiveness to angiotensin II; this may contribute to the reduction in GFR with the two experimental maneuvers. We also tested the interaction between polyol-pathway activation and high dietary protein intake. Aldose reductase inhibition and dietary myo-inositol supplementation had no effect on the component of increased GFR due to 50% dietary protein intake but specifically inhibited the hyperfiltration attributable to diabetes. These results suggest that hyperglycemia acts through increased polyol-pathway activity and its effects on tissue myo-inositol metabolism to play a fundamental role in the pathogenesis of the glomerular hyperfiltration characteristic of early diabetes.