Salt-sensitive blood pressure—an intermediate phenotype predisposing to diabetic nephropathy?

Abstract

Background. Family studies point to important genetic determinants of diabetic nephropathy (DN). Blood pressure (BP) is higher in offspring of patients with type 2 diabetes and DN, but the pathomechanisms involved have not been elucidated. Methods. We examined the salt sensitivity of BP after 5 days equilibration on a low (20 mmol/day) vs high salt diet (220 mmol/day) in three matched groups of 15 subjects each: (i) control individuals; (ii) offspring of type 2 diabetic parents without DN (DNÀ); and (iii) offspring of type 2 diabetic parents with DN (DNþ). Ambulatory BP and hormones involved in sodium homeostasis [plasma renin activity (PRA), aldosterone and atrial natriuretic peptide (ANP)] as well as the tetrahydrocortisol þ 5-allotetrahydrocortisol/tetrahydrocortisone (THF þ 5aTHF)/THE) ratio in the urine as an index of 11b-hydroxysteroid dehydrogenase type 2 (11bHSD2) activity were analysed. Results. In offspring of DNþ patients on a high salt diet, systolic and diastolic BP was 137/82±10/8 mmHg vs 125/77±12/8 mmHg in offspring of DNÀ patients (P<0.01 for systolic BP). The salt-induced difference in mean BP between high and low salt diet was 5.2±3.3 mmHg in offspring of DNþ patients vs 0.7±4.7 mmHg in offspring of DNÀ patients (P<0.002). The proportion of 'salt-sensitive' individuals was 67% in offspring of DNþ patients vs 20% in offspring of DNÀ patients (P<0.05). In all groups, a high salt diet caused a comparable decrease of PRA and p-aldosterone accompanied by an increase in ANP. The urinary (THF þ 5aTHF)/THE ratio was 1.23±0.36 in salt-sensitive individuals and 0.99±0.33 (P<0.03) in salt-resistant subjects, consistent with increased activity of 11bHSD2. Conclusions. BP is more salt sensitive in offspring of type 2 diabetic patients with diabetic nephropathy. The salt sensitivity of BP may be an intermediate phenotype in individuals with a high risk of future diabetic nephropathy.

Sodium, hypertension, and an explanation of the “lag phenomenon” in hemodialysis patients

“…On the contrary, salt removal may be severely restricted in glomerulonephritis, vascular, 72 or diabetic nephropathy. 73,74 Koomans et al 75 studied blood pressure and body fluid volume changes related to salt intake and excretion in patients with glomerulonephritis, polycystic kidney disease, pyelonephritis, nephrosclerosis, analgesic nephropathy, and congenital kidney hypoplasia in various degrees of kidney insufficiency. In these patients, the increase in blood pressure, when related to urinary sodium excretion, rose exponentially with the decrease of creatinine clearance.…”

The unique response of renin and aldosterone to dietary sodium intervention in sodium sensitivity

“…Thus the PRA and aldosterone changes in this study cannot predict long-term responses. Third, the results cannot be extrapolated to subjects with severe hypertension and other medical problems such as diabetes mellitus, 25 because this study enrolled only participants with normotension and stage 1 hypertension without other health problems. Fourth, the small sample size should borne in mind and the results interpreted appropriately.…”

Insulin, CCAAT/Enhancer-Binding Proteins and Lactate Regulate the Human 11β-Hydroxysteroid Dehydrogenase Type 2 Gene Expression in Colon Cancer Cell Lines

“…Furthermore, we recently observed an association of salt-sensitivity and reduced activity of 11beta-HSD2 in offspring of type 2 diabetic patients [9]. Thus, it is reasonable to speculate that insulin downregulates HSD11B2, and by this mechanism, causes cortisol-mediated renal or colonic sodium retention with consequent renin suppression.…”