1998 Global Conference Proceeding
March 02 - 04, 1998
| Conference: | 1998 Global Conference |
|---|---|
| Title: | The Ontogeny and Regulation of AQP2 Gene Expression in the Ovine Fetal Kidney |
| Authors: | Wintour, E. Marelyn; Butkus, A.; Earnest, L.; Jeyasellan, K; Johnson, H.; Moritz, K; Tenis, N |
| Institutions: | Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, National University of Singapore |
The unstressed human or ovine fetus behaves as though it had diabetes insipidus, producing hypotonic urine at a rate of 10 - 20 ml/h/kg body weight. However AVP is synthesized in the hypothalamus by 40 - 50 d (1) and can be released by appropriate stimuli from mid-gestation in the ovine fetus, where term is 145 - 150 days (1,2). AVP receptors (V2) are present at the same concentration and affinity as in the adult during the last third of gestation, and can produce cAMP on stimulation (2). The fetal kidney can produce a hypertonic urine in response to exogenous AVP from 85 - 90 days of gestation, but requires AVP concentrations at least 10 fold those required in adult sheep (3). The relative lack of sensitivity of the fetal kidney to AVP was hypothesized to be due to low levels of the apical water channel protein, aquaporin 2 (AQP2). The ovine AQP2 cDNA was cloned. By Northern Blot analysis, quantified by ratio to GAPDH m RNA, the AQP2 mRNA was first detected at mid-gestation (75-80d) at levels 10% of that in the adult. AQP2 mRNA levels increased three fold by term, and were 81% of adult levels by 10 weeks postpartum. Lower levels of AQP2 mRNA were detectable by PCR from 40 days of gestation, and immunoreactive protein (detected by antibody kindly provided by Dr. Mark Knepper, NIH) was present in collecting ducts from midgestation. Prolonged (3d) infusion of angiotensin 1, in the last third of gestation, induced a significant (P<0.05) (240%) increase in AQP2 mRNA. Whether this is a direct effect on interstitial medullary receptors (AT1 type) known to be present and active in renal growth and differentiation, or whether the increase is secondary to growth effects induced by the diuresis and natriuresis resulting from the prolonged Ang I infusion is unknown. However, it is noteworthy that lower maximal values of AVP are associated with the production of hypertonic urine in stressed fetuses than required when exogenous AVP is infused into unstressed fetuses, and most situations of intrauterine stress (hypoxia, hemorrhage) stimulate increased activation of the renin-angiotensin system and AVP release. In conclusion the nephrogenic diabetes insipidus - like condition of the normal fetus is due to relatively low levels of AQP2 gene expression before birth.
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Supported by Block Grant to HFI from NHMRC, Australia.
Normal human and sheep fetuses behave as though they had diabetes insipidus. Wintour, et. al., studied sheep fetuses to find out why. They found that the antidiuretic hormone, arginine vasopressin (AVP), which is needed to tell the kidneys to concentrate urine and reabsorb body water, is produced in sheep fetuses 40 to 50 days into gestation where term is 150 days. They also found that AVP can be released, given the proper stimulation, from mid-gestation on. The AVP receptors (V2), which are needed to accept AVP's message, are present in the fetus at adult levels during the last third of gestation.
The fetal kidney can respond to injections of AVP, but to do so it requires at least ten times the amount of AVP as does an adult sheep. Wintour, et. al., hypothesized the ten-fold AVP level was needed due to low levels of aquaporin 2 (AQP2) in the fetal kidney. Further testing showed AQP2 levels (as represented by AQP2mRNA) could first be detected 40 days into gestation. At mid-gestation, these levels increased to 10% of adult levels. They reached 30% of adult levels at term and were at 81% of adult levels ten weeks after birth. The authors concluded that the nephrogenic diabetes insipidus-like condition of the normal fetus is due to relatively low levels of AQP2 before birth.