Faculty Bibliography

When a rat with two kidneys is cross-circulated with an anephric rat, compensatory renal hypertrophy occurs as indicated by an increased ratio of RNA to DNA within 6 hours and an increased ratio of kidney weight to body weight within 12 hours. Removal of three kidneys between the rats further increases residual renal mass and RNA/DNA after 24 and 48 hours of cross-circulation as compared with results of removing two kidneys. Trinephrectomy triples the mitotic index and doubles the proliferative index. Increasing the magnitude of renal loss causes appreciable hyperplasia as well as increasing the magnitude of compensatory renal hypertrophy.

Early manifestations of cell proliferation were studied in the large and small bowel of young female rats after resection of the proximal one-third of the small bowel. On the 2nd day after resection, the absolute amounts of RNA and DNA increased in gut distal to the resection. As compared with values from sham-resected gut, nucleic acid levels in much of the distal small bowel and colon increased. Increased specific activity in DNA after injection of [3H]thymidine was present in the small bowel on the 2nd day. Changes were marked and persistent in midgut for 10 days, tending to be less intense and of shorter duration in segments progressively more distal. Compensatory cell proliferation in midgut occurs within 2 days of jejunectomy.

Cytokinetics in colonic mucosa were studied after ileal resection in young female rats. The RNA content of the transverse colon was increased 32% after 7 days; after 14 days the increase was present throughout the colon. The DNA content of the ascending colon increased 29% after 10 days. Specific activity of DNA labeled with [3H-methyl]thymidine was elevated 29% in the ascending colon and elevated 49% in the descending colon on the 7th postoperative day. Colonic cell proliferation is stimulated within 1 week of ileal resection.

Cell proliferation and remodeling of the small intestine were studied after subtotal colectomy in the rat. After an initial fall in nucleic acid contents, there was a trend to increasing amounts of RNA throughout the intestine on the fourteenth postoperative day; by the thirtieth day RNA and DNA contents were increased about 20 percent. DNA synthesis increased after 5 days. Although initially villi became shorter and crypts shallower, higher villi, deeper crypts, and an increased rate of cell migration were present after 14 days. Subtotal colectomy stimulates nucleic acid synthesis and remodeling of the small bowel within 2 weeks. Changes are more marked in ileum.

Catecholamines induce unique growth and secretory responses in salivary glands. An analysis of three enzyme activities involved in cyclic AMP metabolism was carried out to identify the specificity of these responses for salivary glands. Although parotid adenylate cyclase has an unusually high specific activity, its kinetic properties and responses to NaF, guanine nucleotides, and isoproterenol are similar to other tissues not stimulated to grow after isoproterenol stimulation. Solubilized adenylate cyclase was separated from other membrane proteins by isoelectric focusing on polyacrylamide gels. There was a single broad peak of activity with a pI of 5.9. Parotid protein kinase has a subcellular distribution and substrate preference similar to hepatic protein kinase. Activation by cyclic AMP is also similar to that reported for other tissues, with a Ka of 1.2·10-7 M. Parotid cyclic AMP and cyclic GMP phosphoriesterases are a heterogeneous group of enzymes with relatively low specific activity as compared with mouse pancreas, liver and brain. Isoelectric focusing of supernatant phosphodiesterases revealed at least six peaks of enzyme activity in the pI range of 4-6. Previous reports of a large increase in parotid cyclic AMP levels after in vivo administration of catecholamines and specific growth and secretion could be the result of a relatively high specific activity adenylate cyclase associated with low specific activity cyclic AMP phosphodiesterases

The permanence of the early phases of compensatory renal hypertrophy was tested by interrupting vascular parabiosis between an anephric rat and a normal rat after 48 hours. At the time of interruption, the weights and the ratio of ribonucleic acid (RNA) content to deoxyribonucleic acid (DNA) content of the kidneys were the same as those of the remaining kidney in a single rat subjected to unilateral nephrectomy, previously reported. Within 12 hours after parabiosis was stopped, renal mass and nucleic acid concentrations returned to normal. Compensatory hypertrophy could be produced again by unilateral nephrectomy. Regression of the early phase of compensatory hypertrophy appears to be faster than muscular atrophy produced by disuse or denervation. Compensatory hypertrophy can be activated at least twice.

Using [5-3H]orotic acid and [5-3H]uridine as precursors, we compared the efficiency of labeling and the localization of labeled RNA during compensatory hypertrophy of the mouse kidney. [5-3H]orotic acid in tubules labeled RNA 15 times more intensely that [5-3H]uridine, presumably because of greater incorporation of orotic acid into tubular cells. Of the orotic acid label, 97% was in tubular cells, mostly in the proximal tubules. Only about 80% of the uridine label was in the tubules; the ratio in proximal tubules compared with that in distal tubules was 2:1. No changes in distribution within the nephron were produced during compensatory hypertrophy. [5-3H]uridine should be used as the precursor of generalized labeling is desired, but [5-3H5orotic acid is the better precursor of RNA for many studies of compensatory hypertrophy since it is more efficient and concentrates in the segments of greatest biologic activity.