Skin and Kidney Contribute to Salt‐Sensitive Hypertension in the SAME rat

Abstract

Loss of Hsd11b2 causes the syndrome of apparent mineralocorticoid excess (SAME) and salt‐sensitive hypertension, which has been demonstrated in the SAME rat 1. We aimed to determine how salt‐sensitive hypertension developed in young SAME rats.Hsd11b2−/− rats were hypertensive (158 versus 119mmHg controls; measured under anaesthesia) and plasma volume contracted (haematocrit 0.49 versus 0.42 control) by 5 weeks of age and showed profound hypokalemia (2mM plasma K+ versus 4.5mM control) the latter being evident from 15 days of age.Adult kidney RNA‐seq analysis suggested a coordinate down‐regulation of electrolyte and water transporters, while a‐ENaC (Scnn1a; 1.66‐fold), the flow‐induced BK channel (Kcnma1; 2.65‐fold) and the HKA2 channel (Atp12a; 4.29‐fold) were significantly up‐regulated. Young Hsd11b2−/− animals exhibited polydipsia and polyuria from weaning age (~20 days old) and, as with adults, they excreted a higher proportion of ingested Na+ (56%) through the kidney, compared to controls (38%), suggesting that the coordinate changes in nephron transporters are already in place around weaning age.Notably, we observed increased skin electrolytes in neonatal animals, (by drying and ashing pelts and determining electrolytes using atomic absorption spectroscopy). Neonatal Hsd11b2−/− animals retained higher [Na+] in their pelts than the controls.Our data suggest that increased Na+ intake [from mothers’ milk] results in increased Na+ storage in skin at the expense of K+. The ensuing hypokalemia primes the developing nephron to deliver increased Na+ and water to the connecting tubule and cortical collecting duct by weaning age. Glucocorticoid‐induced Na+ uptake in the kidney, and reduced Na+ storage capacity in the pelt, both then contribute to progressive salt‐sensitive hypertension.Support or Funding InformationBritish Heart Foundation Centre of Research Excellence Award (RE/08/001/23904); Kidney Research UK project grant