Glucocorticoid-induced polycystic kidney disease—A threshold trait

McDonald, Alan T. J.; Crocker, John F. S.; Digout, S. C.; McCarthy, Susanna C.; Blecher, Stan R.; Cole, David E. C.

doi:10.1038/ki.1990.64

Cited by 26 publications

(11 citation statements)

References 18 publications

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“…The similar distance of Ke 6 from mammalian 17␤HSD4 and bacterial 7␣HSD, the activity of androgens and estrogens in the kidney, and the evidence that steroid hormones are involved in cyst formation (11)(12)(13)(14)(15)(16)(17) suggested to us that Ke 6 could metabolize a steroid. This prompted us to examine Ke 6 for 17␤HSD activity as described next.…”

Section: Phylogenetic Analysis Shows Ke 6 Is Close To Mammalianmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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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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Section: Phylogenetic Analysis Shows Ke 6 Is Close To Mammalianmentioning

confidence: 99%

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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“…Plausibly, this could be a mechanism for glucocorticoid maturation of renal structure and function, although this remains to be tested. Conversely, high glucocorticoid levels in the perinatal period cause renal cysts (450).…”

Section: Fetal Kidneymentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Chapman

Holmes

Seckl

2013

Physiological Reviews

698

601

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Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

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“…Neonatal mice appear to have a small window of time in which they are susceptible to exogenous forces (i.e. glucocorticoids) inducing the development of a cystic phenotype [39,40]. In slowly progressive PKD, glucocorticoid treatment inhibits the progression of PKD [41].…”

Section: Discussionmentioning

confidence: 99%

Renal dysfunction but not cystic change is ameliorated by neonatal epidermal growth factor in bpk mice

Nakanishi

Gattone

Sweeney

et al. 2001

Pediatric Nephrology

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BALB/c mice homozygous for the bpk gene exhibit a form of autosomal recessive (AR) polycystic kidney disease (PKD) with massive collecting duct cysts, common bile duct dilation and chaotic intrahepatic bile ducts/portal triads. The combined renal and biliary pathology mimics much of the pathology seen in human ARPKD. Murine models of ARPKD generally have a reduced renal expression of epidermal growth factor (EGF) and an increased expression of EGF receptors (EGF-R). However, the role that EGF and EGF-R play in the progression of PKD has been unclear. Evidence from various model systems/ages of treatment produces conflicting results. Treating neonatal C57BL/6J-cpk mice with EGF ameliorates the renal pathology and dysfunction while treating 2- and 3-week-old bpk mice with an EGF-receptor tyrosine kinase inhibitor also ameliorates ARPKD. Therefore, to determine whether neonatal EGF treatment would accelerate or inhibit the progression of the PKD in bpk mice, we administered exogenous EGF (1 microgram/g body weight subcutaneously) daily from postnatal days 3-9 (a critical period for tubule maturation). Neonatal EGF treatment but not sham treatment retarded the development of azotemia and common bile duct dilation and the chaotic hepatic triad changes in cystic mice. However, EGF treatment neither reduced the severity of the renal cystic pathology nor reduced the degree of cystic enlargement of the kidneys. Cystic mice treated past 9 days of age died prior to their scheduled termination at 21 days of age. The role of EGF in the progression of polycystic kidney disease in bpk mice is relatively complicated, with neonatal treatment being associated with some amelioration of the renal dysfunction and extrarenal pathology without an effect on the renal pathology. Continuation of treatment beyond 9 days increased morbidity. Therefore, in discussing the role of EGF or EGF receptor in mediating the pathophysiology of PKD, the stage of development may be an important consideration.

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Glucocorticoid-induced polycystic kidney disease—A threshold trait

Cited by 26 publications

References 18 publications

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

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

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Renal dysfunction but not cystic change is ameliorated by neonatal epidermal growth factor in bpk mice

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