Nephrogenic diabetes insipidus (DI) in a mouse model of renal insufficiency associated with developmental mis‐expression of Six2

Six2 is a developmental transcription factor that influences renal glomerular formation. We reported a radiation‐induced six2 mutant mouse called Br that displays glomerular dysmorphogenesis. This study was carried out to characterize the renal insufficiency associated with six2 mis‐expression in a Br/+ adult. Wildtype (WT) and mutant mice (Br) were separated into four groups: two received 2% NaCl for five days (WT‐S, Br‐S), the others had water (WT‐NS, Br‐NS). Urine composition, plasma osmolality (pOsm) and sodium (pNa + ), and weight change were recorded while immuno‐analysis was undertaken for vasopressin (VP) and cFos in supraoptic neurons (SON). Compared to WT, salt‐loaded heterozygous Br mice: 1) failed to concentrate their urine (WT‐NS: 1640, WT‐S: 2587, Br‐NS: 1605, Br‐S: 1192 mOsm/kg, p <0.01) 2) had a significant increase in pOsm and pNa + (325.4, 332.5, 344.8, 384.2 mOsm/kg, p <0.01; and 131.9, 136.9, 134.2, 145.6 mmol/L, p <0.01) 3) incurred weight loss (33.5, 31.5, 25.5, 19.4 g, p <0.01) and 4) had an increased fluid intake (2.1, 2.0, 2.2, 2.7 ml/10g, p <0.05). Interestingly, no change in VP or cFos expression to increased pNa + was seen in Br‐S animals. Results suggest that developmental mis‐expression of six2 results in a defective kidney in adult animals with reduced urine concentrating capacity and polydipsia, consistent with nephrogenic DI. An uncoupling of VP response to increased pNa + in SON of Br‐S mice warrants further study. Supported by R01 DK064752 (SL)