Renotropic Effect Research Articles

Gender and the effect of gonadal hormones on the progression of inherited polycystic kidney disease in rats

Human autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease and displays a gender dimorphism in renal disease progression. Han:SPRD-Cy rats manifest a form of ADPKD that is similar in many respects to that seen in humans. In Han:SPRD rats, male Cy/+ rats have more prominent renal changes and develop renal failure at an early age, whereas female Cy/+ rats exhibit less severe renal cystic change and have normal renal function until advanced age. To determine whether the male gonadal hormone, testosterone, contributes to this gender dimorphism, males were sham operated or castrated; some castrated rats were repleted with 5a-dihydrotestosterone. Female rats were sham operated or ovariectomized before sham operation or testosterone treatment. All treatments started at 4 weeks of age and ended at 10 weeks of age. Renal enlargement, cystic change, and renal function were assessed. In the males, castration reduced renal enlargement and cystic change; testosterone treatment abrogated these effects. Neither of these manipulations affected azotemia in male Cy/+ rats. In the females, testosterone was renotropic for both normal and cystic kidneys. In the Cy/+ females, testosterone treatment caused azotemia and an increase in the severity of the PKD. Ovariectomy blunted the effect of testosterone on cystic kidney enlargement. Testosterone treatment did not completely erase the gender-associated differences in azotemia in the Cy/+ rat. These data confirm the renotropic effects of testosterone and indicate that testosterone influences the progression of renal cystic change in male and female rats with ADPKD.

The renotropic effect of ovine luteinizing hormone on subtotally nephrectomized rats.

Some of luteinizing hormone (LH) isoforms can stimulate renal growth. The objective of this study is to determine whether the administration of LH modifies subtotal nephrectomy-induced chronic renal failure. Castrated 3/4-nephrectomized male rats were divided into four groups of seven each and fed a low-protein (6%) diet. Ovine LH with renotropic activity (40 micrograms/day) or vehicle only (control) was given for three weeks or six weeks. Compared with controls, remnant kidney weights (% body weight) in LH-treated rats had increased significantly at three weeks (0.385 +/- 0.019 vs 0.443 +/- 0.052, P less than 0.02), but not at six weeks (0.281 +/- 0.004 vs 0.272 +/- 0.013). 24 h creatinine clearance (ml/day/100 g body weight) increased significantly both by three weeks (242 +/- 58 vs 301 +/- 36, P less than 0.05), and six weeks (323 +/- 55 vs 395 +/- 10, P less than 0.01). Urinary thromboxane B2 excretion increased in LH-treated rats, suggesting that hemodynamic changes may play a role in increasing creatinine clearance. Our results suggest that renotropically active oLH stimulated the glomerular function in castrated rats with reduced renal mass. Further study may clarify its clinical usefulness.

Uninephrectomy inducing quantitative and qualitative changes in LH isoforms in the male rat

Recent findings that LH stimulates renal growth have prompted us to examine whether LH exercises renotropic effects on the growing kidney following uninephrectomy. Intact (not castrated) male rats were used for sham uninephrectomy to induce surgical stress suppressing plasma LH and testosterone levels. Compared to sham surgery, uninephrectomy caused a transient 240% increase in plasma LH with a transient increase in plasma testosterone (80%) and in prostate weight on day 2. Although pituitary LH content did not change, chromatofocusing of pituitary extract revealed changed distribution patterns among seven LH isoforms, suggesting selective synthesis or secretion of LH isoforms. Castrated rats were then used so that surgical stress did not affect LH. Uninephrectomy caused sustained increases in plasma LH levels (60-110% increase) for up to six days. Three days after uninephrectomy, pituitary LH content increased significantly (30% increase) with a change in chromatofocusing profiles of LH isoforms. Plasma and pituitary FSH levels did not change. In summary, uninephrectomy changed LH isoforms quantitatively and qualitatively. These changes imply a change in gonadotropic and renotropic activities of LH after uninephrectomy.

The rabbit renotropic system.

Elevated levels of a specific renal growth factor, renotropin, have been associated with spontaneous hypertension. To examine this association more closely, we have undertaken the development of a better assay system to characterize and purify renotropin. Sera from rabbits prior to operation (control) and at a specified time after unilateral nephrectomy (uni) were examined for renotropic activity. Comparing the effects of uni to control sera in the same rabbit, significant stimulation of 3H-thymidine incorporation into the DNA of primary rabbit kidney cultures incubated in D-valine medium to eliminate fibroblast growth was noted: at 3 days postoperatively 73% (n = 13), at 7 days 103% (n = 39), at 10 days 130% (n = 31), at 21 days 101% (n = 24), at 42 days 89% (n = 13). All values were at least P less than 0.01. The stimulatory properties were dose-dependent but reached a plateau at high serum concentrations. Comparing CPM/mg protein in uni/control in different concentrations of sera 7 days postoperatively, uni versus control were 67/44 at 5% v/v, 139/72 at 10% v/v, 261/161 at 20% v/v, and 243/136 at 40% v/v. The renotropic effect of uni sera remained after dialysis in incubation medium and after sera were heated in boiling water for 5 minutes. Renal extracts obtained from growing kidneys 7 days postnephrectomy augmented renotropic activity. Atrial natriuretic factor, ouabain, PGF2 alpha, PGE1, and cAMP did not possess renotropic activity. We conclude that the primary rabbit kidney culture assay for renotropin is highly sensitive and will be an important tool to comprehend the role of renotropin in the pathogenesis of hypertension.

Renotropic activity of lutropin: Direct stimulation of DNA synthesis of cultured rat renal cortical cells

Two differently purified ovine lutropin (LH) preparations were studied to see if they stimulated [ 3H] thymidine incorporation into cultured rat renal cortical cells. Both preparations showed a dose-dependent (0.11–1 ng/ml), time-dependent (peaking at 18 h), serum-dependent (7.5% of fetal calf serum or 10% castrated-hypo-physectomized rat serum) renotropic effect. Ovine TSH and FSH failed to mimic this specific, renotropic effect. We concluded that LH directly stimulates renal DNA synthesis in cooperation with other serum factor's.

Inhibition of sex-steriod hormone induced ornithine decarboxylase and poly(A)polymerase activities by a GnRH agonist in the rat kidney

Recently GnRH and its synthetic agonists were shown to exert extrapituitary actions and inhibit the growth-promoting effects of testosterone and estradiol. In the present study, the long-term effect of GnRH agonist [des-Gly10, D-Ala6-GnRH ethylamide GnRHa] on the steroid-induced renotropic effect was investigated. Gonadectomy of 30-day old male and female rats resulted in the drastic reduction of kidney ornithine decarboxylase (ODC) activity. Injection of testosterone (75 micrograms/rat) or estradiol (1 microgram/rat) to castrated rats significantly increased the enzyme activity at 24 h. Treatment with the GnRH agonist, two doses of 100 micrograms each, caused significant inhibition of the hormone induced ODC activity. Similarly injection of dihydrotestosterone to castrated adult male rats significantly increased poly(A)-polymerase activity at 24 h. Two doses of 100 micrograms of GnRHa caused significant inhibition of DHT induced poly(A)-polymerase activity. These results show that chronic exposure to potent GnRH analogs may have anti-steroidal activity in the kidney.

Metabolic and renotropic effects of human growth hormone in disease.

The renotropic and metabolic effects of human growth hormone were studied in 2 patients with hypopituitarism, 1 with cirrhosis of the liver and 2 with chronic nephritis and usemia. The dosage was 5 to 10 mg. a day for three to nine days. The plasma urea level and urea excretion decreased promptly in all subjects. The blood phosphorus and glucose levels increased gradually, and phosphorus excretion decreased. A renotropic effect was shown by the prompt increases in endogenous creatinine clearance and in phosphorus reabsorption. In the patient with cirrhosis of the liver who had hypocholesterolemia and hypoalbuminemia, the serum cholesterol and albumin levels increased, suggesting that liver function was stimulated. These results emphasize the important role of the growth hormone in adult man, and suggest its use as a therapeutic agent in certain diseased states.

Nonmercurial organic diuretics; their action and application.

The renotropic effect of diuretic agents is employed clinically to induce a more favorable balance between the glomerular filtration of plasma water and the reabsorption of salt and water by the renal tubules. As illustrated in Figure 1, it is attractive to consider that with the pathogenesis of cardiovascular-renal disease there may be phases of progressive imbalance between the reduction in glomerular filtration and the smaller diminution of tubule functional capacity that favors a relatively greater percentage reabsorption of electrolytes and water by the renal tubules. This process may be anticipated to contribute to an increasing percentage reabsorption of the glomerular filtrate leading to the accumulation of fluid in tissues and, ultimately, in body cavities. 1,2 The same net effect would obtain under circumstances where glomerular filtration rate is not necessarily diminished but where there is more than commensurate reabsorption of electrolytes, as under the influence of increased production or

Augmented excretion of urine gonadotrophins during ACTH administration.

SummaryAugmented excretion of urine pituitary gonadotrophins has been demonstrated in 8 of 9 patients receiving ACTH for the treatment of several clinical entities. In the one exception, the doubling of the control gonadotropin titer could not be attributed directly to the effects of the ACTH. Increases of 2 to 8-fold were observed in the remaining patients. The augmentation appeared to be independent of age and sex, was not proportional to the dose of ACTH, and showed irregularities in time of appearance or persistence. In the patient with hypophyseal calcification, the effect was observed on the second day of therapy only which suggested that normal hypophyseal function was essential for the increased excretion. The known reno-tropic effect of the adrenal steroids was considered the most probable explanation for the observed changes.

Renotropic effects of some androgens upon experimental hydronephrosis and upon the clitoris in the mouse.

The growth-stimulating effects of androgenic steroids upon the renal parenchyma and their influence upon some of its metabolic functions have long been known and have recently been reviewed by Henderson (1949). Renotropic effects of androgens, particularly those of testosterone propionate upon the diseased kidney in experimental hydronephrosis (Selye, 1940), sublimate poisoning (Selye, 1941) and in man in the uremia of cholera (Henderson, 1949) have been described. The present study was undertaken in an attempt to utilize the property of the experimental hydronephrotic kidney of being susceptible to “protection” by steroid hormones as a simple means to evauate the relative renotropic potency of such compounds. Simultaneously, effects of some androgens upon the weights of other organs in intact animals were investigated. A good correlation between dosage and effect was found to exist between testosterone and the weight of the clitoris: It is thought that this may furnish a simultaneous measurement of the a...

Methylandrostenediol: a non-virilizing derivative of testosterone in metastatic cancer of the breast.

Methylandrostenediol was chosen for clinical trial in patients with metastatic cancer of the breast because it was the first of a series of compounds tested which on bioassay showed renotropic effects on experimental hydronephrosis in female adult mice resembling those of testosterone propionate. The method and results of these bioassays will be published elsewhere(l). The marked degree of protection afforded the tubular epithelial cells by testosterone propionate and methylandrostenediol in experimental hydronephrosis is illustrated in Fig. 1. This renotropic property of methylandrostenediol is at present under investigation in human renal disorders. Testosterone, vinyl testosterone, cis testosterone, testosterone tocap-tate and testosterone carbonate failed to give such renal protection. Methylandrostenediol was given to 7 women with metastasizing cancer of the breast for periods of 1 to 7 months, and in doses varying from 25 mg in oil given intramuscularly to 100 mg per day intramuscularly in aqueous suspension. The latter dose was found to be clinically the most effective. Pellets of 60 mg implanted every 20 to 30 days were also used. The maximal total dose was 10 g given intramuscularly in aqueous suspension.§ The patients were women ranging in age from 34 to 64 years, in whom cancer of the breast had been diagnosed as being of from 1 to 8 years duration prior to the initiation of methylandrostenediol therapy. Subjective improvement with varying degrees of euphoria and a sense of well-being occurred in all cases and lasted for from 1 to 7 months under therapy. Objective clear-cut calcification of bone lesions studied by X-ray was found in 2 patients and one is shown in Fig. 2 and 3. Soft tissue lesions regressed in 2 other instances under methylandrostenediol therapy. Studies of blood chemistry (phosphorus, calcium, alkaline phosphatase, NPN and total protein) showed trends comparable to those seen in the course of chemotherapy of breast cancer with testosterone and are illustrated in Fig. 4.

Nephrotoxic and Renotropic Effects of Lead on White Rats and its Prevention by B.A.L

There have been many studies on renal injuries produced by lead, but so far as we are aware, mention has never been made of a renotropic effect of lead.

THE BENEFICIAL ACTION OF TESTOSTERONE IN EXPERIMENTAL RENAL ATROPHY CAUSED BY LIGATURE OF THE URETER

AFTER IT HAD BEEN SHOWN that various steroid hormones, especially the androgens,exert a definite “renotropic” action inasmuch as they cause an enlargement of the kidney tubules (I, 2, 3), it became of interest to establish whether this renotropic effect could be used pharmacologically in cases in which a stimulation of the renal tissue is desirable. Animal experiments showed that testosterone exerts a protective action against the kidney damaging effect of sublimate (4) and that the compensatory renal hypertrophy following unilateral nephrectomy is considerably increased by testosterone propionate treatment (5). In continuation of these investigations the question arose whether the renal atrophy, which is normally caused by ligature of one ureter, could be delayed by androgen treatment. This problem appeared of some practical importance inasmuch as we felt that it might lead to an interesting clinical application of the renotropic steroids in the comparatively frequent condition of hydronephrosis with sub...