Hsp70 and Hsp90 Multichaperone Complexes Sequentially Regulate Thiazide-sensitive Cotransporter Endoplasmic Reticulum-associated Degradation and Biogenesis

Donnelly, Bridget F.; Needham, Patrick G.; Snyder, Avin C.; Roy, Ankita; Khadem, Shaheen; Brodsky, Jeffrey L.; Subramanya, Arohan R.

doi:10.1074/jbc.m113.455394

Cited by 54 publications

(48 citation statements)

References 51 publications

(62 reference statements)

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“…CHX chase assays in HEK-293T cells were carried out as described previously (62). For chase assays in the presence of the proteasome inhibitor MG-132, transiently transfected cells were pretreated with 10 μM MG-132 or DMSO vehicle control for 4 hours, prior to the initiation of the chase.…”

Section: Discussionmentioning

confidence: 99%

“…HEK-293T cell culture and transfection protocols were carried out as described previously (62). Cells were analyzed 24-48 hours after transfection.…”

Section: Discussionmentioning

confidence: 99%

“…Immunoblot analysis was performed as described previously (62). Freshly dissected kidneys were flash frozen prior to analysis, and homogenates were prepared as described (63).…”

Section: Discussionmentioning

confidence: 99%

“…Coimmunoprecipitation studies in HEK-293T and mpkCCD c14 cells were performed with antibodyconjugated resins or protein A/G agarose, as described (62).…”

Section: Discussionmentioning

confidence: 99%

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Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action

Roy

Al‐Qusairi

Donnelly

et al. 2015

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

“…HEK-293T cell culture and transfection protocols were carried out as described previously (62). Cells were analyzed 24-48 hours after transfection.…”

Section: Discussionmentioning

confidence: 99%

“…Immunoblot analysis was performed as described previously (62). Freshly dissected kidneys were flash frozen prior to analysis, and homogenates were prepared as described (63).…”

Section: Discussionmentioning

confidence: 99%

“…Coimmunoprecipitation studies in HEK-293T and mpkCCD c14 cells were performed with antibodyconjugated resins or protein A/G agarose, as described (62).…”

Section: Discussionmentioning

confidence: 99%

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Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action

Roy

Al‐Qusairi

Donnelly

et al. 2015

Journal of Clinical Investigation

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“…Most Gitelman mutations introduce changes into the NCC polypeptide that cause the cotransporter to misfold (12). This results in enhanced recognition by a molecular chaperone protein called Hsp70, which binds to misfolded NCC as it is being made in the endoplasmic reticulum and targets it for degradation (13,14).…”

Section: Mechanism Of Na 1 Reabsorption In the Dct Apical Sodium Tranmentioning

confidence: 99%

Distal Convoluted Tubule

Subramanya

Ellison

2014

Clinical Journal of the American Society of Nephrology

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185

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The distal convoluted tubule is the nephron segment that lies immediately downstream of the macula densa. Although short in length, the distal convoluted tubule plays a critical role in sodium, potassium, and divalent cation homeostasis. Recent genetic and physiologic studies have greatly expanded our understanding of how the distal convoluted tubule regulates these processes at the molecular level. This article provides an update on the distal convoluted tubule, highlighting concepts and pathophysiology relevant to clinical practice.

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Molecular Genetics of Gitelman Syndrome

Colussi

Tedeschi

Bettinelli³

et al. 2014

Encyclopedia of Life Sciences

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Gitelman syndrome (OMIM 263800 ) is an autosomal recessive renal tubular disorder due to loss‐of‐function mutations of SLC12A3 gene, encoding the thiazide‐inhibitable, electroneutral Na + ‐Cl − cotransporter (NCC) of the distal convoluted tubule. Clinical consequences include chronic normotensive hypokalemic alkalosis, hypomagnesemia, hypocalciuria, polyuria/nocturia, chronic asthenia, muscular cramps, chondrocalcinosis and rarely cardiac arrhythmias. Impaired reabsorption of glomerular filtrate through NCC drives preferential reabsorption of Na + in more distal tubular segments via the ‘electrogenic’ channel ENaC, enhancing tubular secretion of potassium and protons, explaining the hypokalemic alkalosis. There exists wide variability and severity of symptoms between subjects, ranging from an almost asymptomatic disease to a severely disabling one. More than 400 SLC12A3 mutations have been so far described, evenly distributed along the protein sequence and without any hot spot. Mutation detection rate actually is approximately 80–90%. There are no genotype–phenotype correlations. Commonly considered a benign condition, Gitelman syndrome may be associated with reduced quality of life, increased medicalisation and high hospitalisation rate. Key Concepts: Gitelman syndrome is the clinical and biochemical manifestation of impaired function of the electroneutral Na‐Cl cotransporter of the renal distal convoluted tubule, the target of the thiazide class of diuretics. Homozygous and compound heterozygous loss‐of‐function mutations of the SLC12A3 gene cause the disease; more than 400 inactivating mutations (mostly missense mutations) have been identified, without any preferential target. Main biochemical abnormalities include hypokalemia, mild metabolic alkalosis, hypomagnesemia, hyperreninemia and hypocalciuria. Clinical manifestations include muscular cramps/tetanic crisis, asthenia, polyuria/nocturia and chondrocalcinosis; normal/low blood pressure is an important feature in the differential diagnosis with hypertensive hypokalemic disorders. Gitelman syndrome cannot be presently cured, and therapy aims at correcting plasma potassium and possibly magnesium levels with supplemental oral potassium and magnesium, aldosterone receptor antagonists and the sodium channel blocker amiloride. Intravenous infusions of potassium and magnesium are needed in acute crisis and stressful contexts. Long‐term prognosis appears good and long‐term renal function preserved, but quality of life may be somehow impaired and medicalisation/hospitalisation rate increased compared to the general population.

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Hsp70 and Hsp90 Multichaperone Complexes Sequentially Regulate Thiazide-sensitive Cotransporter Endoplasmic Reticulum-associated Degradation and Biogenesis

Cited by 54 publications

References 51 publications

Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action

Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action

Distal Convoluted Tubule

Molecular Genetics of Gitelman Syndrome

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