| First Author | Grill A | Year | 2016 |
| Journal | Acta Physiol (Oxf) | Volume | 218 |
| Issue | 3 | Pages | 198-211 |
| PubMed ID | 27421685 | Mgi Jnum | J:259681 |
| Mgi Id | MGI:6149095 | Doi | 10.1111/apha.12755 |
| Citation | Grill A, et al. (2016) Salt-losing nephropathy in mice with a null mutation of the Clcnk2 gene. Acta Physiol (Oxf) 218(3):198-211 |
| abstractText | AIM: The basolateral chloride channel ClC-Kb facilitates Cl reabsorption in the distal nephron of the human kidney. Functional mutations in CLCNKB are associated with Bartter''s syndrome type 3, a hereditary salt-losing nephropathy. To address the function of ClC-K2 in vivo, we generated ClC-K2-deficient mice. METHODS: ClC-K2-deficient mice were generated using TALEN technology. RESULTS: ClC-K2-deficient mice were viable and born in a Mendelian ratio. ClC-K2-/- mice showed no gross anatomical abnormalities, but they were growth retarded. The 24-h urine volume was increased in ClC-K2-/- mice (4.4 +/- 0.6 compared with 0.9 +/- 0.2 mL per 24 h in wild-type littermates; P = 0.001). Accordingly, ambient urine osmolarity was markedly reduced (590 +/- 39 vs. 2216 +/- 132 mosmol L(-1) in wild types; P < 0.0001). During water restriction (24 h), urinary osmolarity increased to 1633 +/- 153 and 3769 +/- 129 mosmol L(-1) in ClC-K2-/- and wild-type mice (n = 12; P < 0.0001), accompanied by a loss of body weight of 12 +/- 0.4 and 8 +/- 0.2% respectively (P < 0.0001). ClC-K2-/- mice showed an increased renal sodium excretion and compromised salt conservation during a salt-restricted diet. The salt-losing phenotype of ClC-K2-/- mice was associated with a reduced plasma volume, hypotension, a slightly reduced glomerular filtration rate, an increased renal prostaglandin E2 generation and a massively stimulated renin-angiotensin system. Clckb-/- mice showed a reduced sensitivity to furosemide and were completely resistant to thiazides. CONCLUSION: Loss of ClC-K2 compromises TAL function and abolishes salt reabsorption in the distal convoluted tubule. Our data suggest that ClC-K2 is crucial for renal salt reabsorption and concentrating ability. ClC-K2-deficient mice in most aspects mimic patients with Bartter''s syndrome type 3. |
