Polycystic Renal Disease: A New Experimental Model

Perey, Daniel Y. E.; Herdman, Roger; Good, Robert A.

doi:10.1126/science.158.3800.494

Cited by 74 publications

(20 citation statements)

References 6 publications

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“…Administrationi of these steroids to fetal and neonatal animals cain seriously iml)air Olrgalnl anid somiatic growth and neurologic functioni (12)(13)(14)(15)(16)(17)(18). Only somiie of these effects are 1)artially or fully reversed by comlpenisatory catclh-up growstlh after witlhdrawal of steroid (12,13,16,17,30).…”

Section: Discussionmentioning

confidence: 99%

“…However, the doses of lhormlone per kilogram body w-eiglht used in the animal studies are 15-300 times that which the human fetus receives xvith prenatal betamethlasonie therapy. This is a critical consideration since the extent of the effects in animals is dose related (12,13,18 (6,32).…”

Section: Discussionmentioning

confidence: 99%

“…These bindin-proteins are saturated by physiolog,ic levels of corticosteroidls, suggesting that the (lesire(d nmaturational effects slhould he accomplished without the use of pharmacologic doses of steroid. This is anlnil)ortant conlsi(leratioln silnce it is knlowII that large (loses of corticosteroids inhibit growvth in many organs of fetal ancd neoinatal aninlds (12)(13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

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Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome.

Ballard¹,

Granberg²,

Ballard³

1975

J. Clin. Invest.

211

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A B S T R A C T Serumii glucocorticoid levels were (letermined in 20 inothers andI 43 premature infalnts wh-lio r-eceived prenatal betamnetlhasonie therapy for preventionl of respiratory distress syndrome (RDS). 'Maternal betamethasone peaked at 75 ,ug cortisol equivalents per 100 ml 1 h after injection of 12 mg steroid and declined to half by 6 h. Betamethasone in cord blood w-as 14.3 tig cortisol equivalents per 100 ml at 1 h, decreased to a level of 4.7 at 20 h, aand was not detected 2 days after a second dose at 24 h. After the second dose, the mean level of cortisol in cord blood was 5.9 yg per 100 ml compared witlh 13.05 y-per 100 ml (P < 0.001) in untreated premature infanits. The unbound glucocorticoid activity in treated infants delivered 1-10 h after the second dose (mean, 8.4 Ag per 100 nil) is simlilar to the unbound cortisol level after birth in untreated premature infants who develop RDS.These findings indicate that (a) serlum glucocorticoid levels in the physiologic stress range can induce lung mnaturationi in the human aind (b) antenatal treatment with this dose of betaimietlhasoine does not expose the lhuman fetuis to potentially hiarmiftil pharmacologic levels of steroid.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome.

Ballard¹,

Granberg²,

Ballard³

1975

J. Clin. Invest.

211

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“…The involvement of a steroid dehydrogenase in renal cyst formation is particularly intriguing since previously several laboratories had demonstrated that the rodent kidney is extremely vulnerable to cyst formation in response to steroid administration at a critical time in development (11)(12)(13)(14)(15)(16)(17). Moreover, the cystogenic potential of glucocorticoids has been directly demonstrated in metanephric kidneys in organ culture by us (5) and others (18).…”

mentioning

confidence: 99%

Characterization of Ke 6, a New 17β-Hydroxysteroid Dehydrogenase, and Its Expression in Gonadal Tissues

Fomitcheva¹,

Baker²,

Anderson³

et al. 1998

Journal of Biological Chemistry

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The abnormal regulation of the Ke 6 gene has been linked to the development of recessive polycystic kidney disease in the mouse. In this report, we have shown that Ke 6 is a 17␤-hydroxysteroid dehydrogenase and can regulate the concentration of biologically active estrogens and androgens. The Ke 6 enzyme is preferentially an oxidative enzyme and inactivates estradiol, testosterone, and dihydrotestosterone. However, the enzyme has some reductive activity and can synthesize estradiol from estrone. We find that the Ke 6 gene is expressed within the ovaries and testes. The presence of Ke 6 protein within the cumulus cells surrounding the oocyte places it in a strategic location to control the level of steroids to which the egg is exposed. Previously, it had been shown that glucocorticoids can induce renal cysts in the neonatal rodent, only when given at a narrow time window of postnatal kidney development. We propose that the reduction in the level of Ke 6 enzyme, which occurs in the cpk, jck, and pcy mice, may lead to abnormal elevations in local level of sex steroids, which either directly or indirectly via abnormal glucocorticoid metabolism result in recessive renal cystic disease, a developmental disorder of the kidney.The Ke 6 gene, encoded within the major histocompatibility complex, has been intimately linked to the development of cysts in the kidney and liver of mice (1-6). The expression of the Ke 6 gene is severely down-regulated in all murine models of PKD 1 that have been examined to date: cpk, jck (1, 3) and pcy mice (2). The inhibition of the Ke 6 gene expression using antisense deoxyoligonucleotides in embryonic kidneys in organ cultures gives rise to numerous cysts against a background of normal nephrogenesis (5, 6). Importantly, the human Ke 6 gene is located on chromosome 6p21 (7) where the human autosomal recessive PKD mutation has been mapped (8) and therefore there is a possibility that the Ke 6 gene is the primary mutation in autosomal recessive PKD. The structure of the mouse Ke 6 gene (2), cDNA (1), and protein (4) has been extensively characterized in our laboratory.Our earlier data base searches with the Ke 6 sequence showed that it belongs to the short-chain dehydrogenase/reductase family (1). At that time, Ke 6 was most similar to bacterial oxidoreductases with no close similarity to any mammalian oxidoreductase in the data base, leaving the exact function of Ke 6 unknown. Recently, we searched the data base again with Ke 6 and found it is similar to 17␤HSD4 (9). This prompted us to examine Ke 6 for 17␤HSD activity with various androgen and estrogen substrates.As reported here, we find that Ke 6 protein is an NAD-dependent 17␤HSD, making it the seventh member of this class of enzyme. It efficiently catalyzes the oxidation of estradiol, testosterone, and dihydrotestosterone and also the reduction of estrone to form biologically active estradiol. The identification of the substrate of Ke 6 allows us to postulate that regulated sex steroid metabolism plays a crucial role in the development o...

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“…These clinical observations are interesting, although mechanistic explanations are limited. Small subcortical renal cysts can be induced in rabbits (50,51) and rats (52) by the administration of glucocorticoids, a phenotype that is reversed by the coadministration of potassium supplements and correction of hypokalemia, thus implicating hypokalemia as responsible for renal growth on the basis of other observations that hypokalemia leads to increased renal weight through tubuloepithelial hyperplasia and hypertrophy (53,54). It is not certain what implications these data have on the care of patients with ADPKD.…”

Section: Possible Associations Between Cystic Kidney Diseases and Primentioning

confidence: 99%

A Young Patient with a Family History of Hypertension

Peixoto¹

2014

Clinical Journal of the American Society of Nephrology

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The evaluation of causes of hypertension in young adults with a family history of hypertension needs to be methodical to identify potentially treatable causes. Renal-and renovascular imaging and measurement of plasma aldosterone and plasma renin activity are at the core of this evaluation in most patients. Pertinent aspects of hypertension in autosomal dominant polycystic kidney disease are discussed with a focus on the role of the endothelium in mediating early hypertension and a review of treatment strategies. Finally, the possibility that autosomal dominant polycystic kidney disease and primary aldosteronism are connected beyond coincidence is explored; evidence to support it is scant, although there is a likely role for aldosterone excess and the resultant hypokalemia in promoting cyst growth.Clin J Am Soc Nephrol 9: 2164-2172, 2014. doi: 10.2215/CJN.02240314 Case PresentationA 36-year-old white man presented for the evaluation of hypertension, hypokalemia, and biochemical evidence of aldosterone excess. His hypertension was first diagnosed at 22 years of age while in the military, and we do not have records of his evaluation at that time. He reported that he had BP levels in the 150/100-mmHg range and that his weight at that time was approximately 180 lb (body mass index [BMI] approximately 24.5 kg/m 2 ). He was treated with lisinopril with prompt and sustained achievement of BP control.He left the military when he was 26 years old, and his new physician performed an evaluation of his hypertension. He was asymptomatic. He reported a family history of hypertension starting in early adulthood in his brother, mother, one maternal uncle, and maternal grandfather. He was not aware of any history of strokes, kidney disease, endocrine tumors, or hypokalemia, although he had been estranged from his parents since early childhood, and therefore, the information about his family was not complete.His BP was 128/84 mmHg. Other than being overweight (218 lb; BMI529.4 kg/m 2

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Polycystic Renal Disease: A New Experimental Model

Cited by 74 publications

References 6 publications

Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome.

Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome.

Characterization of Ke 6, a New 17β-Hydroxysteroid Dehydrogenase, and Its Expression in Gonadal Tissues

A Young Patient with a Family History of Hypertension

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