Pendrin: linking acid base to blood pressure.

Pendrin (SLC26A4) is an anion exchanger from the SLC26 transporter family which is mutated in human patients affected by Pendred syndrome, an autosomal recessive disease characterized by sensoneurinal deafness and hypothyroidism. Pendrin is also expressed in the kidney where it mediates the exchange of internal HCO for external Cl at the apical surface of renal type B and non-A non-B-intercalated cells. Studies using pendrin knockout mice have first revealed that pendrin is essential for renal base excretion.

Dominant negative mutation in oxalate transporter associated with enteric hyperoxaluria and nephrolithiasis.

Background: Nephrolithiasis (NL) is a complex multifactorial disease affecting up to 10%-20% of the human population and causing a significant burden on public health systems worldwide. It results from a combination of environmental and genetic factors. Hyperoxaluria is a major risk factor for NL.

Identification of ATP6V1C2 as a novel candidate gene for distal tubular acidosis.

Young onset distal tubular acidosis is a rare genetic disorder that can lead, if untreated, to many complications. Mutations in few genes account for almost half of the cases, whereas the molecular mechanisms accounting for the remaining cases are still unknown. The present study reports the use of whole-exome sequencing to identify new dRTA-causing genes and demonstrates that inactivating mutations in the ATP6V1C2 gene impair renal proton pump function.

Tubular Acidification Defect in Adults with Sickle Cell Disease.

Background And Objectives: Metabolic acidosis is a frequent manifestation of sickle cell disease but the mechanisms and determinants of this disorder are unknown. Our aim was to characterize urinary acidification capacity in adults with sickle cell disease and to identify potential factors associated with decreased capacity to acidify urine.

Design, Setting, Participants, & Measurements: Among 25 adults with sickle cell disease and an eGFR of ≥60 ml/min per 1.

Acute genetic ablation of pendrin lowers blood pressure in mice.

Background: Pendrin, the chloride/bicarbonate exchanger of β-intercalated cells of the renal connecting tubule and the collecting duct, plays a key role in NaCl reabsorption by the distal nephron. Therefore, pendrin may be important for the control of extracellular fluid volume and blood pressure.

Methods: Here, we have used a genetic mouse model in which the expression of pendrin can be switched-on in vivo by the administration of doxycycline.

The ClC-K2 Chloride Channel Is Critical for Salt Handling in the Distal Nephron.

Chloride transport by the renal tubule is critical for blood pressure (BP), acid-base, and potassium homeostasis. Chloride uptake from the urinary fluid is mediated by various apical transporters, whereas basolateral chloride exit is thought to be mediated by ClC-Ka/K1 and ClC-Kb/K2, two chloride channels from the ClC family, or by KCl cotransporters from the SLC12 gene family. Nevertheless, the localization and role of ClC-K channels is not fully resolved.

Double Knockout of the Na+-Driven Cl-/HCO3- Exchanger and Na+/Cl- Cotransporter Induces Hypokalemia and Volume Depletion.

We recently described a novel thiazide-sensitive electroneutral NaCl transport mechanism resulting from the parallel operation of the Cl/HCO exchanger pendrin and the Na-driven Cl/2HCO exchanger (NDCBE) in β-intercalated cells of the collecting duct. Although a role for pendrin in maintaining Na balance, intravascular volume, and BP is well supported, there is no in vivo evidence for the role of NDCBE in maintaining Na balance. Here, we show that deletion of NDCBE in mice caused only subtle perturbations of Na homeostasis and provide evidence that the Na/Cl cotransporter (NCC) compensated for the inactivation of NDCBE.

Renal β-intercalated cells maintain body fluid and electrolyte balance.

Inactivation of the B1 proton pump subunit (ATP6V1B1) in intercalated cells (ICs) leads to type I distal renal tubular acidosis (dRTA), a disease associated with salt- and potassium-losing nephropathy. Here we show that mice deficient in ATP6V1B1 (Atp6v1b1-/- mice) displayed renal loss of NaCl, K+, and water, causing hypovolemia, hypokalemia, and polyuria. We demonstrated that NaCl loss originated from the cortical collecting duct, where activity of both the epithelial sodium channel (ENaC) and the pendrin/Na(+)-driven chloride/bicarbonate exchanger (pendrin/NDCBE) transport system was impaired.

Overexpression of pendrin in intercalated cells produces chloride-sensitive hypertension.

Inherited and acquired disorders that enhance the activity of transporters mediating renal tubular Na(+) reabsorption are well established causes of hypertension. It is unclear, however, whether primary activation of an Na(+)-independent chloride transporter in the kidney can also play a pathogenic role in this disease. Here, mice overexpressing the chloride transporter pendrin in intercalated cells of the distal nephron (Tg(B1-hPDS) mice) displayed increased renal absorption of chloride.