A family study of congenital nephrogenic diabetes insipidus combined with hyperuricemia / 中华内分泌代谢杂志

Objective:To investigate the clinical and genetic characteristics, pathogenesis and treatment strategy of congenital nephrogenic diabetes insipidus(CNDI)combined with hyperuricemia.Methods:The clinical manifestations and laboratory data of an infant patient diagnosed as CNDI with hyperuricemia and his family members were collected and retrospectively analyzed. Whole exome sequencing(WES)was applied to detect the proband′s genome variation of each exon and suspected variants of AVPR2 and ABCG2 were verified by PCR-Sanger sequencing of members from his pedigree. Furthermore, we retrospectively collected the serum uric acid levels of patients(≤14-year-old) with CNDI in the First Affiliated Hospital of Zhengzhou University from January 2015 to January 2022.Results:The proband was clinically diagnosed with CNDI and the rest of the family members had no symptoms of polydipsia or polyuria. In addition to the proband, his father was also suffered from hyperuricemia. WES showed that the proband carried a hemizygous AVPR2 gene variation(p.S331R)and a heterozygous ABCG2 gene variation(p.N308K). The former was X-linked recessive inheritance from his mother, and the latter was autosomal dominant inheritance from the father. Fraction excretion of uric acid(FEUA)of the proband and his father with hyperuricemia were 3.1% and 2.7%, respectively. Twelve children(≤14-year-old)were diagnosed with CNDI from the respective study. Among all the cases, 11 patients were male and 1 was female, ranging from 3-month to 14-year-old. Five patients were accompanied with hyperuricemia.Conclusion:Children with CNDI may be complicated with hyperuricemia, and the regimen of hydrochlorothiazide combined with benzbromarone is effective. The pathogenicity of the AVPR2 gene variation(p.S331R)and ABCG2 gene variation(p.N308K)in this pedigree needs to be further studied.

Mechanism of Suoquanwan on Enuresis Based on Network Pharmacology and Experimental Verification / 中国实验方剂学杂志

Objective:To explore the targets and relevant signaling pathways of Suoquanwan in the treatment of enuresis using network pharmacology，and animal expriments are applied to further define its mechanism of action. Method:Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform（TCMSP） database was used to screen out active chemical components of Suoquanwan，varieties of systematic biological databases were integrated to construct the "active component-disease-target" network relationship，and the common protein protein interaction network（PPI） network genes were functionally enriched. Quantitative real time polymerase chain reaction（Real-time PCR） and Western blot were used to verify the effect of Suoquanwan on AVPR2 and DRD2 gene. Result:A total of 32 active ingredients were screened from Suoquanwan. These active ingredients were interacted with 131 potential targets relating to Enuresis，which contained 14 core target genes，namely arginine vasopressin receptor 2 （AVPR2）， neurotrophic receptor tyrosine kinase 1（NTRK1）， dopamine receptor D2（DRD2）， opioid receptor mu 1（OPRM1）， 5-hydroxytryptamine receptor 1A（HTR1A）， 5-hydroxytryptamine receptor 1B（HTR1B），solute carrier family 6 member 4（SLC6A4），Adrenoceptor Alpha 2A（ADRA2A）， prostaglandin-endoperoxide synthase 2（PTGS2）， cholinergic receptor muscarinic 2（CHRM2）， solute carrier family 6 member 3 （SLC6A3）， 5-hydroxytryptamine receptor 6（HTR6）， solute carrier family 6 member 2（SLC6A2）， cytochrome P450 family 2 subfamily C member 19（CYP2C19）. Gene enrichments mainly involved to G protein-coupled receptor signaling pathway，regulation of trans-synaptic signaling，regulation of neurotransmitter transport and neuroactive ligand-receptor interaction. Real-time PCR and Western blot results showed that Suoquanwan could enhance the expression of AVPR2 in rat kidney，and weaken the expression of DRD2 in rat adrenal. Conclusion:The main chemical constituents in Suoquanwan may alleviate enuresis by regulating AVPR2 and DRD2 and then participating in the G protein-coupled receptor signaling pathway，regulation of trans-synaptic signaling，regulation of neurotransmitter transport and other biological processes.

X-linked congenital renal diabetes insipidus caused by AVPR2 gene mutation: a case report / 天津医药

@#Objective A case of congenital renal diabetes insipidus caused by mutation of arginine vasopressin receptor 2 (AVPR2) gene was reported to explore the clinical significance of AVPR2 gene mutation in congenital nephrotic diabetes insipidus and improve the understanding of the disease. Methods The clinical data of proband and his parents were retrospectively analyzed, and the related literature was reviewed. All exons of AVPR2 were amplified by PCR, and the amplified products were purified and sequenced in two directions. Results The clinical manifestations of the children were recurrent fever and hypernatremia, and hyperchloremia was difficult to correct. There was no abnormality in pituitary nuclear magnetic resonance in the child at the beginning. Short T1 signal disappeared in the posterior pituitary lobe after reexamination. Central diabetes insipidus was not excluded from clinical practice. However, vasopressin test supported renal diabetes insipidus, which caused troubles in clinical diagnosis. The treatment of vasopressin acetate tablets was ineffective. The results of gene analysis confirmed that mutations were found in the subregion of AVPR2 gene in the proband: c.359T (thymine)>G (guanine) caused amino acid changes: p.Met120Arg, which was located on the X chromosome, and the mother of the patient was the carrier of the mutation of AVPR2 gene. Clinical application of hydrochlorothiazide and amiloride in the treatment of the child with urinary volume significantly reduced, confirmed as congenital renal diabetes insipidus. Conclusion Congenital renal diabetes insipidus in infants and young children is rare and its clinical manifestations are not specific. It can only be manifested by repeated fever and electrolyte disturbance, which causes troubles in clinical diagnosis. AVPR2 gene detection can be used for screening and gene diagnosis of congenital renal diabetes insipidus.

Preclinical Efficacy of V⁴Q⁵dDAVP, a Second Generation Vasopressin Analog, on Metastatic Spread and Tumor-Associated Angiogenesis in Colorectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Control of metastatic spread of colorectal cancer (CRC) remains as a major therapeutic challenge. [V4 Q5 ]dDAVP is a vasopressin peptide analog with previously reported anticancer activity against carcinoma tumors. By acting as a selective agonist of arginine vasopressin type 2 membrane receptor (AVPR2) present in endothelial and tumor cells, [V⁴Q⁵]dDAVP is able to impair tumor aggressiveness and distant spread. Our aim was to evaluate the potential therapeutic benefits of [V⁴Q⁵]dDAVP on highly aggressive CRC disease using experimental models with translational relevance. MATERIALS AND METHODS: Murine CT-26 and human Colo-205 AVPR2-expressing CRC cell lines were used to test the preclinical efficacy of [V⁴Q⁵]dDAVP, both in vitro and in vivo. RESULTS: In syngeneic mice surgically implanted with CT-26 cells in the spleen, sustained intravenous treatment with [V⁴Q⁵]dDAVP (0.3 µg/kg) dramatically impaired metastatic progression to liver without overt signs of toxicity, and also reduced experimental lung colonization. The compound inhibited in vivo angiogenesis driven by Colo-205 cells in athymic mice, as well as in vitro endothelial cell migration and capillary tube formation. [V⁴Q⁵]dDAVP exerted AVPR2-dependent cytostatic activity in vitro (IC₅₀ 1.08 µM) and addition to 5-fluorouracil resulted in synergistic antiproliferative effects both in CT-26 and Colo-205 cells. CONCLUSION: The present preclinical study establishes for the first time the efficacy of [V⁴Q⁵]dDAVP on CRC. These encouraging results suggest that the novel second generation vasopressin analog could be used for the management of aggressive CRC as an adjuvant agent during surgery or to complement standard chemotherapy, limiting tumor angiogenesis and metastasis and thus protecting the patient from CRC recurrence.

A Case of Congenital Nephrogenic Diabetes Insipidus Confirmed by Gene Analysis / 소아과

Nephrogenic diabetes insipidus (NDI) is a disorder in which the secretion of antidiuretic hormone is normal, but the response of the renal collecting tubules to vasopressin is impaired. Compared with acquired NDI (a-NDI), which is secondary to chronic bilateral incomplete urinary tract obstruction with hydronephrosis, congenital NDI (c-NDI) is a very rare heritable disorder that usually follows the X- linked recessive pattern. Clinical symptoms of c-NDI can be non specific, and often the disease ultimately results in failure to thrive, or mental retardation. Recently, the diagnosis can be confirmed by direct sequencing analysis of the peripheral blood specimens. The long-term results of treatment for c-NDI are not satisfactory. Reports on the follow up of c-NDI cases are rare and there is no report on the cases treated with combinations of three drugs. We report herein a case of severe c-NDI in an 8 year-old-boy with a severely dysconfigurated urinary tract system. The patient and his mother showed a frameshift mutation on the AVPR2 gene on chromosome Xq28: .847_851delTGCTG (p.C283fsX90). The patient showed normal growth and development by treatment with combinations of hydrochlorothiazide (65 mg/m2), amiloride (0.3 mg/kg/d) and indomethacin (100 mg/m2), yet after five years he needed adjuvant cystostomy to relieve him from the residual symptoms of urgency with polyuria.