With the development of molecular biology and clinical medicine, there has been further understanding of the genetic and etiologic pathogenesis of urolithiasis. In the past 10 years, the research hotspots related to the diagnosis and treatment of urolithiasis have focused on the study of mutated loci and related protein functions in the molecular biology of urolithiasis pathogenesis. Regarding the therapeutic aspects of urolithiasis, the main focus is on the study of the formulation of the ADH analogue DDAVP. As for the gene therapy of congenital nephrogenic uremia, the main focus is to find the molecular chaperones of the proteins encoded by the relevant mutated genes, so that the mutant receptors can be expressed on the cell membrane and, after binding to the ligand, exert the corresponding biological effects through the mediation of cAMP, which are currently limited to cytological studies and have not been used in animal experiments and clinical applications. This section introduces the progress about the molecular biology and genetics of urogenital disorders. I. Regulation of secretion, action and control of antidiuretic hormone 1. Regulation of water balance by ADH (antidiuretic hormone, arginine pressor, AVP in humans) There is a great variation in water intake and excretion in the human body, however, plasma osmolality as well as plasma volume fluctuate within a rather narrow physiological range. In the regulation of water balance, AVP secreted by the hypothalamus and pituitary gland plays a key role. In the kidney, the glomerulus is capable of filtering approximately 180 liters of water per day. About 80% and 15% of this water is reabsorbed in the proximal and distal tubules of the kidney, respectively. Thus, approximately 9 L of hypotonic urine per day reaches the collecting ducts of the kidney. AVP produced by the hypothalamus and pituitary gland facilitates the reabsorption of primary urine by binding to AVP receptors in the collecting ducts, thereby concentrating the urine and maintaining the final volume of urine excreted between 2 and 3 L per day in normal individuals. AVP is a hormone secreted by the hypothalamus and pituitary gland and is regulated by the AVP-NPII gene, which is 2.6 kb in length. The precursor of AVP is synthesized in the membrane-bound ribosomes of large cell neurons in the hypothalamus. during intracellular transport, the signal peptide dissociates from the AVP precursor and releases the AVP precursor in the endoplasmic reticulum. the AVP precursor enters the Golgi apparatus for glycosylation and is then transported to the posterior pituitary for storage in secretory vesicles and post-transport processing. AVP stored in the posterior pituitary gland is released into the blood when blood volume and plasma osmolality are altered. Plasma AVP exerts its physiological effects by binding to specific AVP receptors. AVP receptors include three types: V1, V2 and V3. The expression of V2 receptors is highly tissue-specific. v1 receptors are mainly found in vascular smooth muscle cells, hepatocytes and platelets and are involved in glycogenolysis, platelet aggregation and vascular tone regulation. v2 receptor expression is restricted to the epithelial cells of the ascending branches of renal Henry’s collaterals and collecting ducts, and the expression of v2 mRNA in collecting ducts is 10 times higher than that of Henry’s collaterals. When AVP binds to V2 receptors, intracellular cAMP levels increase, mediating the antidiuretic effect of AVP. V3 receptors are mainly located in the anterior pituitary, and AVP promotes ACTH release by acting on these receptors. AVP controls water reabsorption by controlling the number of water channels located at the top of the cell membrane of the distal convoluted tubules and collecting ducts. When AVP binds to V2R, it enhances the cAMP-dependent protein kinase phosphorylation cascade in renal collecting duct principal cells by activating adenylate cyclase, which increases the level of the second messenger cAMP and promotes the formation of aqueous channel proteins in the luminal membrane of the principal cells. Due to the difference in osmotic pressure between the lumen of the collecting duct and the renal interstitium, water in primary urine enters the main cell from the collecting duct through the water channel protein, which concentrates urine. 2, Control regulation of ADH release Plasma osmolality is the most important factor in the regulation of AVP release under physiological conditions. In turn, blood sodium levels play a key role. It has been demonstrated that the threshold of plasma osmolality for AVP release when antidiuresis occurs is 287 mOsm/kg. the threshold of plasma osmolality for the onset of thirst is 290-294 mOsm/kg. at this time the plasma concentration of AVP can reach 5.0 ng/L, and at this time the kidneys also reach the maximum antidiuretic effect of AVP in full effect, and the urine is fully concentrated until the urine osmolality reaches Thereafter, even if the plasma AVP concentration rises again, its antidiuretic effect will not be enhanced. Blood volume and blood pressure are another important factor in regulating AVP release. When blood volume decreases by 10% or less, it can trigger the release of AVP and induce water drinking. As blood volume decreases, the plasma concentration of AVP can be higher than the release of AVP induced by 10 times higher osmolarity. Many hypothalamic neuromediators and neuropeptides can regulate the secretion of AVP. The nicotinic affinity of acetylcholine for supraoptic neurons stimulates the release of AVP. Histamine, bradykinin and angiotensin II can stimulate the release of AVP and stimulate drinking. Many drugs stimulate AVP release, including nicotine, morphine, vincristine, vincristine, cyclophosphamide, antamine, chlorosulfonylurea, and tricyclic anticonvulsants and antidepressants. Glucocorticoids and AVP have antagonistic effects on water excretion, and cortisol increases the release threshold of AVP. Glucocorticoids can prevent water intoxication and correct the water diuretic impairment response to water load in adrenal cortical insufficiency. Glucocorticoids also act directly on the renal tubules, reducing water permeability and increasing solute and free water excretion in AVP deficiency. II. Definition of Diabetes Insipidus (DI) is a group of clinical syndromes in which the kidneys excrete large amounts of dilute urine (generally, urine volume exceeds 30 ml/kg/24hrs, while urine osmolality is less than 300 mOsm/kg or urine specific gravity is less than 1.010). The causes of DI can be insufficient ADH production (central DI), impaired ADH action (nephrogenic DI), or physiologically inhibited ADH release due to excessive water load (primary polydipsia). Third, the classification of DI 1, central uremia (cranial, neurogenic, central or vasopressin-responsive) also known as brain-derived, neurogenic, central or vasopressin-responsive DI). (1) Definition Central dysuria is a state of polyuria with low osmolality resulting from insufficient or deficient ADH secretion despite the presence of adequate stimulation and a good renal response to ADH. These include: complete central uremia (a state of polyuria caused by the complete inability of the body to synthesize or release ADH) and partial central uremia (a state of polyuria caused by the inability of the body to synthesize and/or release sufficient ADH). (2) Etiology The causes of central uremia can be divided into two categories: familial (congenital) and acquired central uremia. a. Molecular biology and genetic studies of familial central enuresis Autosomal dominant familial central enuresis (adFNDI) is the main etiology of congenital central enuresis. adFNDI is a rare autosomal dominant disorder. It is caused by mutations in the AVP-II gene in hypothalamic neuronal cells, resulting in impaired synthesis, folding, dimerization, processing and secretion of AVP, resulting in a deficiency of plasma AVP. Patients with AVP deficiency usually start in childhood, with no significant gender differences and a mean age of onset of 3.2 years [3], and exhibit progressive clinical symptoms such as thirst, excessive drinking and polyuria. The clinical symptoms include progressive thirst, polyuria and polyuria. The general 24-hour urine output can reach 6.6-28.8 liters. The AVP-NPII gene is localized on chromosome 20p13 and it consists of three exons: exon 1 encodes the signal peptide of 19 peptides, the AVP of 9 peptides, 3 peptide linkers and the first 9 amino acid residues of the amino terminus of NPII; exon 2 encodes a conserved region of NPII with 67 amino acid residues; exon 3 encodes 17 amino acid residues of the carboxy terminus of NPII, an Arg linker and the 39 amino acid glycoprotein GP-copeptin. Since 1991, when mutations in AVP-NPII were first identified by Ito [8] and others, 29 mutation sites in AVP-NPII have been identified in 43 families. Most of these mutation sites are mutations in the domain encoding NPII, with four cases occurring in exon 1 of the signal peptide and only one mutation in the nine-peptide AVP itself [9]. Most of these mutations were missense mutations, five cases were nonsense mutations (all occurred in the NPII structural domain near the glycoprotein region), and three cases were deletion mutations. Based on the above-mentioned multiplicity of mutations in the AVP-NPII gene, the pathogenesis of CDI may be that each mutation has a significant effect on the processes of synthesis, folding, dimerization, processing and secretion of the encoded AVP-NPII protein, making the AVP incapable of correct expression and secretion. These findings have been confirmed by cytological and experimental studies in knockout mice. b. Acquired central dysuria: for more causes of central dysuria. The largest group of cases reported internationally on the etiology of central uremia is the etiology of 408 patients with central uremia reported at Peking Union Medical College Hospital from 1956 to 2000. Among them, idiopathic uremia accounted for 52%; saddle area tumor accounted for 28%; CDI due to cranial trauma accounted for 8%; CDI after intracranial infection accounted for 4%; postoperative and ischemic lesions in the saddle area accounted for 3% respectively; and histiocytosis X accounted for 2%. 2, nephrogenic DI (1) Definition Nephrogenic DI is a state of polyuria in which the kidneys are insensitive to the action of ADH, resulting in a continuous discharge of low osmolarity urine. It is clinically characterized by an organism that exhibits persistent hypotonic urine despite adequate levels of ADH in the blood. It is unresponsive to exogenous ADH or can be responsive in some patients with nephrogenic enuresis. It is also divided into complete nephrogenic uremia (the kidney does not respond to ADH or exogenous drugs at all) and partial nephrogenic uremia (the kidney responds to pharmacological doses of ADH). (2) Etiology Nephrogenic uremia can also be classified as familial or acquired nephrogenic uremia.