Clinical and genetic analysis of a case of Gitelman syndrome accompanied with Graves disease and adrenocortical adenoma: A case report.

RATIONALE: Gitelman syndrome (GS), also known as familial hypokalemia and hypomagnesemia, is a rare autosomal recessive inherited disease caused by primary renal desalinization caused by impaired reabsorption of sodium and chloride ions in the distal renal tubules. We report a case of clinical and genetic characteristics of GS accompanied with Graves disease and adrenocorticotrophic hormone (ACTH)-independent adrenocortical adenoma. PATIENT CONCERNS: The patient is a 45 year old female, was admitted to our hospital, due to a left adrenal gland occupying lesion as the chief complaint. DIAGNOSIS: The patient was finally diagnosed as GS with Graves disease and adrenocortical adenoma. INTERVENTIONS: Potassium magnesium aspartate (1788 mg/d, taken orally 3 times a day (supplement a few times a day, intake method, treatment duration). Contains 217.2 mg of potassium and 70.8 mg of magnesium, and potassium chloride (4.5 g/d, taken orally 3 times a day (supplement a few times a day, intake method, and treatment duration); Potassium 2356 mg), spironolactone (20 mg/d, taken orally once a day (supplement a few times a day, intake method, treatment duration). After 3 months of treatment, the patient's blood potassium fluctuated between 3.3-3.6 mmol/L, and blood magnesium fluctuated between 0.5-0.7 mmol/L, indicating a relief of fatigue symptoms. OUTCOMES: On the day 6 of hospitalization, the symptoms of dizziness, limb fatigue, fatigue and pain were completely relieved on patient. In the follow-up of the following year, no recurrence of the condition was found. LESSONS: The novel c.1444-10(IVS11)G > A variation may be a splicing mutation. The compound heterozygous mutations of the SLC12A3 gene may be the pathogenic cause of this GS pedigree.

[Genetic analysis of two patients with Gitelman syndrome].

OBJECTIVE: To explore the genetic etiology of two patients with Gitelman syndrome (GS). METHODS: Two patients who had presented at the Linyi People's Hospital in January and June 2022 respectively were selected as the study subjects. Peripheral blood samples of them were collected and subjected to whole exome sequencing (WES). Electrolyte levels in their serum and urine were detected. Candidate variants were verified by Sanger sequencing. PyMOL software was used to predict the impact of the variants on the protein structure. RESULTS: Patient 1 was a 27-year-old female with decreased serum levels of sodium, potassium, chloride and magnesium, along with decreased urine chloride and calcium. WES revealed that she has harbored compound heterozygous variants of the SLC12A3 gene, namely c.1456G>A (p.D486N) and c.179C>T (p.T60M). The former was inherited from her mother and known to be pathogenic. Patient 2 was a 4-year-old male with lower serum sodium, chloride and magnesium levels, and his serum potassium level was found to be critically low. He was found to harbor compound heterozygous variants of c.602-16G>A and c.805_806insTTGGCGTGGTCTCGGTCA (p.V268_T269insIGVVSV) of the SLC12A3 gene, which were inherited from his mother and father, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics, both variants were predicted to be pathogenic (PVS1+PM2_Supporting+PP3; PVS1+PM2_Supporting+PM4). CONCLUSION: The above heterozygous variants of the SLC12A3 gene probably underlay the GS in these patients.

Interpreting epigenetic causes of recurrent hypokalemia and seizures: Gitelman syndrome co-exist with pseudohypoparathyroidism type 1B.

We describe a unique case of 27-year-old male with Gitelman syndrome (GS) co-exist with pseudohypoparathyroidism type 1B (PHP1B). The patient presented with a 5-year history of seizures, tetany, and numbness of the extremities. Further examinations showed recurrent hypokalemia, inappropriate kaliuresis, hypocalcemia, hyperphosphatemia, and elevated PTH levels. A novel variant of autosomal recessive GS (p.Val287Met SLC12A3) and a novel 492.3Kb deletion containing the whole of STX16, were discovered by a whole-exome sequencing. Following the diagnosis, calcitriol, calcium, and potassium supplements were started. Hematuria calcium and phosphorus levels, as well as blood potassium levels, have recovered and remained within normal ranges after 3 years of follow-up. Our findings have important consequences for supporting the idea that heterozygosity for variants have effects on the patients' clinical performance with autosomal recessive inheritance disorders. Further study is need for the putative effects of the variant. Likewise, further investigation with regards to the gene-gene interaction relations between GS and other electrolyte imbalance disorders is warranted.

Long-Term Indomethacin Treatment in a Chinese Child with Gitelman Syndrome: Case Report and Literature Review on its Efficacy and Tolerance.

BACKGROUND Gitelman syndrome (GS) is a rare inherited autosomal recessive salt-losing renal tubulopathy. Early-onset GS is difficult to differentiate from Bartter syndrome (BS). It has been reported in some cases that cyclooxygenase (COX) inhibitors, which pharmacologically reduce prostaglandin E2(PGE2) synthesis, are helpful for GS patients, especially in children, but the long-term therapeutic effect has not yet been revealed. CASE REPORT A 4-year-old boy was first brought to our hospital for the chief concern of short stature and growth retardation. Biochemical tests demonstrated severe hypokalemia, hyponatremia, and hypochloremic metabolic alkalosis. The patient's serum magnesium was normal. He was diagnosed with BS and treated with potassium supplementation and indomethacin and achieved stable serum potassium levels and slow catch-up growth. At 11.8 years of age, the patient showed hypomagnesemia and a genetic test confirmed that he had GS with compound heterozygous mutations in the SLC12A3 gene. At the age of 14.8 years, when indomethacin had been taken for nearly 10 years, the boy reported having chronic stomachache, while his renal function remained normal. After proton pump inhibitor and acid inhibitor therapy, the patient's symptoms were ameliorated, and he continued to take a low dose of indomethacin (37.5 mg/d divided tid) with good tolerance. CONCLUSIONS Early-onset GS in childhood can be initially misdiagnosed as BS, and gene detection can confirm the final diagnosis. COX inhibitors, such as indomethacin, might be tolerated by pediatric patients, and long-term therapy can improve the hypokalemia and growth retardation without significant adverse effects.

Gitelman syndrome combined with diabetes mellitus: A case report and literature review.

RATIONALE: Gitelman syndrome (GS) is an uncommon autosomal recessive tubulopathy resulting from a functional deletion mutation in the SLC12A3 gene. Its onset is typically insidious and challenging to discern, and it is characterized by hypokalemia, metabolic alkalosis, and reduced urinary calcium excretion. There is limited literature on the diagnosis and management of GS in individuals with concomitant diabetes. PATIENT CONCERNS: A 36-year-old male patient with a longstanding history of diabetes exhibited suboptimal glycemic control. Additionally, he presented with concurrent findings of hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. DIAGNOSIS: Building upon the patient's clinical manifestations and extensive laboratory evaluations, we conducted thorough genetic testing, leading to the identification of a compound heterozygous mutation within the SLC12A3 gene. This definitive finding confirmed the diagnosis of GS. INTERVENTIONS: We have formulated a detailed medication regimen for patients, encompassing personalized selection of hypoglycemic medications and targeted electrolyte supplementation. OUTCOMES: Following 1 week of comprehensive therapeutic intervention, the patient's serum potassium level effectively normalized to 3.79 mmol/L, blood glucose parameters stabilized, and there was significant alleviation of clinical symptoms. LESSONS: GS has a hidden onset and requires early diagnosis and intervention based on patient related symptoms and laboratory indicators in clinical practice, and personalized medication plans need to be provided according to the specific situation of the patient.

[Clinical and genetic analysis of a case of Gitelman syndrome with comorbid Graves disease and adrenocortical adenoma].

OBJECTIVE: To report the clinical and genetic characteristics of a rare case of Gitelman syndrome with comorbid Graves disease and ACTH-independent adrenocortical adenoma. METHODS: A patient who had presented at the Nanchong Central Hospital on December 21, 2020 was selected as the study subject. Clinical data of the patient was collected. Whole-exome sequencing was carried out on DNA extracted from peripheral venous blood samples from the patient and her family members. RESULTS: The patient, a 45-year-old woman, was found to have Graves disease, ACTH-independent Cushing syndrome, hypokalemia and hypomagnesemia following the discovery of an adrenal incidentaloma. MRI scan had revealed a 3.8 cm × 3.2 cm mass in the left adrenal gland. The mass was removed by surgery and confirmed as adrenocortical adenoma. DNA sequencing revealed that the patient and her sister have both harbored compound heterozygous variants of the SLC12A3 gene, namely c.1444-10(IVS11)G>A and c.179(exon1)C>T (p.T60M), which were respectively inherited from their father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.1444-10(IVS11)G>A and c.179(exon1)C>T (p.T60M) were respectively classified as a variant of uncertain significance (PM2_Supporting+PP3) and a likely pathogenic variant (PM3_Strong+PM1+PP3). CONCLUSION: The conjunction of Gitelman syndrome with Graves disease and adrenal cortex adenoma is rather rare. The newly discovered c.1444-10(IVS11)G>A variant of the SLC12A3 gene, together with the heterozygous variant of c.179(exon1)C>T (p.T60M), probably underlay the pathogenesis in this patient.

Novel heterozygous mutations of SLC12A3 gene in a Chinese pedigree with Gitelman syndrome: A care-compliant case report.

RATIONALE: The diagnosis of Gentleman syndrome (GS) is usually delayed because the clinical symptoms are easily mistaken. PATIENT CONCERNS: A 19-year-old male patient was referred to endocrinology due to intermittent twitch of extremities for approximately 7 years. DIAGNOSES: The diagnosis of GS was made based on the laboratory and gene detection results. We identified 2 new variants in the SLC12A3 gene [c.857 A > C (exon7) and c.2089_2095del (exon17)] in his Asian family. INTERVENTIONS: The patient received the treatment of potassium chloride sustained release tablets, potassium magnesium aspartate and spironolactone. After given potassium supplement through enema, his serum potassium level was corrected to normal. OUTCOMES: The electrolyte imbalance including hypokalemia and hypomagnesemia were improved with a remission of the clinical manifestations. But the patient's condition still could not remain stable for his irregular oral potassium supplementation during the follow-up of nearly 3 months. LESSONS: Our finding broadens the variant spectrum of SLC12A3 and contributes to a more quickly genetic counseling. As a result, when a patient presents with persistent, unspecified, and inadequately treated hypokalemia, tests for GS should indeed be considered. For suspected cases of GS, genetic testing should always be considered in the diagnosis.

Spectrum of variants in a large Chinese Gitelman syndrome cohort.

Gitelman syndrome (GS) is caused by SLC12A3 biallelic variants. A previous study showed that large rearrangements (LRGs) of SLC12A3 accounted for the low sensitivity of genetic testing. However, a systematic screening for LRGs in Chinese GS patients is lacking. Massively parallel sequencing (MPS) and multiplex ligation-dependent probe amplification (MLPA) were performed to sequence the genomic DNA of patients with clinically diagnosed GS. Of 165 index cases, MPS identified 151 cases with two or more affected alleles and 14 cases with one variant allele. LRGs were detected by MLPA in 20 out of 27 cases, including 15 cases with suspected LRGs by MPS. Among these 20 cases with LRGs, the results of MPS and MLPA were identical in only 8 cases. Additional LRGs in 6 cases were detected by MLPA alone. In 6 cases, E4_E6del was identified by MPS, while E4_E5del and Intron6del were identified by MLPA. Among the 102 distinct variants, 30 are novel. LRGs were found in 20 cases (12.1%). LRGs were found in 12.1% of our Chinese GS patients cohort. We show that MPS and MLPA are two complementary techniques with the ability to improve the diagnostic yield of GS.

Case report: Gitelman syndrome with diabetes: Confirmed by both hydrochlorothiazide test and genetic testing.

RATIONALE: Gitelman syndrome (GS) is an autosomal recessive tubulopathy caused by mutations of the SLC12A3 gene. It is characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. Hypokalemia, hypomagnesemia, and increased renin-angiotensin-aldosterone system (RAAS) activity can cause glucose metabolism dysfunction. The diagnosis of GS includes clinical diagnosis, genetic diagnosis and functional diagnosis. The gene diagnosis is the golden criterion while as functional diagnosis is of great value in differential diagnosis. The hydrochlorothiazide (HCT) test is helpful to distinguish GS from batter syndrome, but few cases have been reported to have HCT testing. PATIENT CONCERNS: A 51-year-old Chinese woman presented to emergency department because of intermittent fatigue for more than 10 years. DIAGNOSES: Laboratory test results showed hypokalemia, hypomagnesemia, hypocalciuria and metabolic alkalosis. The HCT test showed no response. Using next-generation and Sanger sequencing, we identified 2 heterozygous missense variants (c.533C > T:p.S178L and c.2582G > A:p.R861H) in the SLC12A3 gene. In addition, the patient was diagnosed with type 2 diabetes mellitus 7 years ago. Based on these findings, the patient was diagnosed with GS with type 2 diabetic mellitus (T2DM). INTERVENTIONS: She was given potassium and magnesium supplements, and dapagliflozin was used to control her blood glucose. OUTCOMES: After treatments, her fatigue symptoms were reduced, blood potassium and magnesium levels were increased, and blood glucose levels were well controlled. LESSONS: When GS is considered in patients with unexplained hypokalemia, the HCT test can be used for differential diagnosis, and genetic testing can be continued to confirm the diagnosis when conditions are available. GS patients often have abnormal glucose metabolism, which is mainly caused by hypokalemia, hypomagnesemia, and secondary activation of RAAS. When a patient is diagnosed with GS and type 2 diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) can be used to control the blood glucose level and assist in raising blood magnesium.

Gitelman syndrome with Graves' disease leading to rhabdomyolysis: a case report and literature review.

A 14-year-old male patient who suffered from limb numbness, fatigue, and hypokalemia was considered Graves' disease (GD) complicated with thyrotoxic periodic paralysis (TPP) at the first diagnosis. Although with the treatment of antithyroid drugs, he developed severe hypokalemia and rhabdomyolysis (RM). Further laboratory tests revealed hypomagnesemia, hypocalciuria, metabolic alkalosis, hyperrenin, and hyperaldosteronemia. Genetic testing revealed compound heterozygous mutations in the SLC12A3 gene (c.506-1G > A, c.1456G > A) encoding the thiazide-sensitive sodium-chloride cotransporter, which presented a definitive diagnosis of Gitelman syndrome (GS). Moreover, gene analysis revealed his mother diagnosed with subclinical hypothyroidism due to Hashimoto's thyroiditis carried the c.506-1G > A heterozygous mutation in the SLC12A3 gene and his father carried the c.1456G > A heterozygous mutation in the SLC12A3 gene. His younger sister who had hypokalemia and hypomagnesemia carried the same compound heterozygous mutations as the proband and was diagnosed with GS as well, but with a much milder clinical presentation and better treatment outcome. This case suggested the potential relationship between GS and GD, clinicians should strengthen the differential diagnosis to avoid missed diagnosis.

[Regulation of kidney on potassium balance and its clinical significance].

Virtually all of the dietary potassium intake is absorbed in the intestine, over 90% of which is excreted by the kidneys regarded as the most important organ of potassium excretion in the body. The renal excretion of potassium results primarily from the secretion of potassium by the principal cells in the aldosterone-sensitive distal nephron (ASDN), which is coupled to the reabsorption of Na+ by the epithelial Na+ channel (ENaC) located at the apical membrane of principal cells. When Na+ is transferred from the lumen into the cell by ENaC, the negativity in the lumen is relatively increased. K+ efflux, H+ efflux, and Cl- influx are the 3 pathways that respond to Na+ influx, that is, all these 3 pathways are coupled to Na+ influx. In general, Na+ influx is equal to the sum of K+ efflux, H+ efflux, and Cl- influx. Therefore, any alteration in Na+ influx, H+ efflux, or Cl- influx can affect K+ efflux, thereby affecting the renal K+ excretion. Firstly, Na+ influx is affected by the expression level of ENaC, which is mainly regulated by the aldosterone-mineralocorticoid receptor (MR) pathway. ENaC gain-of-function mutations (Liddle syndrome, also known as pseudohyperaldosteronism), MR gain-of-function mutations (Geller syndrome), increased aldosterone levels (primary/secondary hyperaldosteronism), and increased cortisol (Cushing syndrome) or deoxycorticosterone (hypercortisolism) which also activate MR, can lead to up-regulation of ENaC expression, and increased Na+ reabsorption, K+ excretion, as well as H+ excretion, clinically manifested as hypertension, hypokalemia and alkalosis. Conversely, ENaC inactivating mutations (pseudohypoaldosteronism type 1b), MR inactivating mutations (pseudohypoaldosteronism type 1a), or decreased aldosterone levels (hypoaldosteronism) can cause decreased reabsorption of Na+ and decreased excretion of both K+ and H+, clinically manifested as hypotension, hyperkalemia, and acidosis. The ENaC inhibitors amiloride and Triamterene can cause manifestations resembling pseudohypoaldosteronism type 1b; MR antagonist spironolactone causes manifestations similar to pseudohypoaldosteronism type 1a. Secondly, Na+ influx is regulated by the distal delivery of water and sodium. Therefore, when loss-of-function mutations in Na+-K+-2Cl- cotransporter (NKCC) expressed in the thick ascending limb of the loop and in Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule (Bartter syndrome and Gitelman syndrome, respectively) occur, the distal delivery of water and sodium increases, followed by an increase in the reabsorption of Na+ by ENaC at the collecting duct, as well as increased excretion of K+ and H+, clinically manifested as hypokalemia and alkalosis. Loop diuretics acting as NKCC inhibitors and thiazide diuretics acting as NCC inhibitors can cause manifestations resembling Bartter syndrome and Gitelman syndrome, respectively. Conversely, when the distal delivery of water and sodium is reduced (e.g., Gordon syndrome, also known as pseudohypoaldosteronism type 2), it is manifested as hypertension, hyperkalemia, and acidosis. Finally, when the distal delivery of non-chloride anions increases (e.g., proximal renal tubular acidosis and congenital chloride-losing diarrhea), the influx of Cl- in the collecting duct decreases; or when the excretion of hydrogen ions by collecting duct intercalated cells is impaired (e.g., distal renal tubular acidosis), the efflux of H+ decreases. Both above conditions can lead to increased K+ secretion and hypokalemia. In this review, we focus on the regulatory mechanisms of renal potassium excretion and the corresponding diseases arising from dysregulation.

A case report of Gitelman syndrome in children.

RATIONALE: Giltelman syndrome (GS) is an autosomal recessive infectious disease, which is caused by the mutation of SLC12A3 gene encoding thiazide diuretic sensitive sodium chloride cotransporter located in the distal convoluted tubule of the kidney. PATIENT CONCERNS: A 7-year-old and 3-month-old male patient has poor appetite, slow growth in height and body weight since the age of 3, body weight: 16 kg (-3 standard deviation), height: 110 cm (-3 standard deviation), normal exercise ability and intelligence. One year ago, he was diagnosed with hypokalemia. After potassium supplement treatment, the blood potassium returned to normal. The patient developed abdominal pain, vomiting, limb weakness, and tetany 1 day before admission. DIAGNOSES: After admission examination, the patient was found to have hypokalemia (2.27-2.88 mmol/L), hypomagnesemia (0.47 mmol/L), hypophosphatemia (1.17 mmol/L), hypocalcemia (1.06 mmol/24 hours), and metabolic alkalosis (PH 7.60). The blood pressure is normal, and the concentration of aldosterone is 791.63 pg/mL. The adrenocorticotropic hormone and cortisol detected at 8 am are 4.95 pmol/L and 275.09 nmol/L, respectively. Twenty-four hours of urine potassium is 32.52 mmol. Gene sequencing results showed 2 pathogenic variants in the GS-related SLC12A3 gene, which are related to the phenotype of the subject. INTERVENTIONS: After admission, the patients were given potassium and magnesium supplements, as well as oral spironolactone. The symptoms of limb weakness and tetany were significantly relieved. After discharge, the patients continued to maintain treatment to keep the blood potassium at more than 3.0 mmol/L, and the blood magnesium at more than 0.6 mmol/L. OUTCOMES: Follow-up at 1 month after discharge, in the patient's self-description, he had no symptoms such as limb weakness and tetany, and his height was increased by 1 cm and the body weight increased by 1.5 kg. LESSONS: For patients with hypokalemia, hypomagnesemia, and metabolic alkalosis, the possibility of GS should be given priority. After the diagnosed by gene sequencing of SLC12A3 gene, potassium and magnesium supplementation could significantly improve symptoms.

Síndrome de Gitelman: cuándo sospecharlo / Gitelman syndrome, when to suspect it

Las tubulopatías son un grupo heterogéneo de entidades definidas por anomalías de la función tubular renal. El síndrome de Gitelman, objeto de nuestro artículo, está causado por mutaciones inactivantes del gen SLC12A3, que codifica el cotransportador Na-Cl sensible a tiazidas del túbulo contorneado distal, produciendo así una pérdida urinaria de Cl-Na. Se exponen tres casos clínicos de síndrome de Gitelman, cada uno con una clínica de presentación. La finalidad de este artículo es sensibilizar al lector en esta tubulopatía y ayudar en su diagnóstico precoz (AU)

Tubulopathies are a heterogeneous group of entities defined by abnormalities of renal tubular function. Gitelman syndrome, the subject of our article, is caused by inactivating mutations of the SLC12A3 gene, which encodes the thiazide-sensitive Na-Cl cotransporter of the distal convoluted tubule, thus producing a urinary loss of Cl-Na.Three clinical cases of Gitelman syndrome are presented, each with a clinical presentation. The purpose of this article is to familiarize the reader with this tubulopathy and to help in its early diagnosis. (AU)

Total colectomy for poorly controlled hypokalaemia due to Gitelman syndrome.

Gitelman syndrome (GS) is an autosomal recessive tubulopathy caused by dysfunction of the thiazide-sensitive sodium-chloride cotransporter, which leads to hypokalaemia, metabolic alkalosis, hypomagnesaemia and hypocalciuria. Patients with GS show varied clinical features due to hypokalaemia: tetany, muscle weakness, periodical paralysis and constipation, which is one of the most frequent ones. This paper presents the case of a woman in her 40s referred to our endocrinology department for severe hypokalaemia. After biochemical and genetic analyses, a diagnosis of GS was established. Concurrently, the patient suffered from refractory constipation due to hypokalaemia and underwent a total colectomy with ileorectal anastomosis, which cured both disorders without any medication for 3 years.

Clinicopathological Features of Gitelman Syndrome with Proteinuria and Renal Dysfunction.

INTRODUCTION: Gitelman syndrome (GS) is a rare renal tubular salt-wasting disorder. Besides kidney electrolyte loss, proteinuria and renal dysfunction were also observed. However, their incidence, risk factors, pathological features, and prognosis were unclear. METHODS: We retrospectively reviewed 116 GS patients and analyzed their clinical, genetic, and pathological characteristics. We also systematically reviewed articles on GS with proteinuria and renal dysfunction. RESULTS: Twenty-three GS patients had proteinuria (69.6%) and renal dysfunction (43.5%) with a mean age of 35.3 ± 13.2 years, and 65.2% were male. Compared to patients without proteinuria or renal dysfunction, these patients had elevated plasma angiotensin II level (440.2 ± 351.7 vs. 253.2 ± 187.4 pg/mL, p = 0.031) and three times higher incidence of diabetes. The renal pathology of nine biopsied patients indicated hypertrophy of the juxtaglomerular apparatus (100%), chronic tubulointerstitial changes (66.7%), intrarenal vascular changes (66.7%), and glomerulopathy (55.6%). More extensive renin staining was observed in patients with GS than in the control group with glomerular minor lesion (p < 0.001). During a median of 85 months (range, 11-205 months) of follow-up for 19 out of the 23 GS-renal patients, the renal function was generally stable, except one died of cancer and one developed end-stage renal disease because of concomitant membranous nephropathy and IgA nephropathy. CONCLUSION: Proteinuria and renal dysfunction were more common than expected and might indicate glomerulopathy and vascular lesions besides a tubulointerstitial injury in GS. Renal function may maintain stable with effective therapy in most cases.

Structure and thiazide inhibition mechanism of the human Na-Cl cotransporter.

The sodium-chloride cotransporter (NCC) is critical for kidney physiology1. The NCC has a major role in salt reabsorption in the distal convoluted tubule of the nephron2,3, and mutations in the NCC cause the salt-wasting disease Gitelman syndrome4. As a key player in salt handling, the NCC regulates blood pressure and is the target of thiazide diuretics, which have been widely prescribed as first-line medications to treat hypertension for more than 60 years5-7. Here we determined the structures of human NCC alone and in complex with a commonly used thiazide diuretic using cryo-electron microscopy. These structures, together with functional studies, reveal major conformational states of the NCC and an intriguing regulatory mechanism. They also illuminate how thiazide diuretics specifically interact with the NCC and inhibit its transport function. Our results provide critical insights for understanding the Na-Cl cotransport mechanism of the NCC, and they establish a framework for future drug design and for interpreting disease-related mutations.