Molecular changes in proximal tubule function in diabetes mellitus

1. Diabetic kidney disease is initially associated with hypertension and increased urinary albumin excretion. The hypertension is mediated by enhanced volume expansion due to enhanced salt and water retention by the kidney. The increased urinary albumin is not only due to increased glomerular leak, but also to a decrease in albumin reabsorption by the proximal tubule. The precise molecular mechanisms underlying these two phenomena and whether there is any link between the increase in Na+ retention and proteinuria remain unresolved. 2. There is significant evidence to suggest that increased Na+ retention by the proximal tubule Na+/H+ exchanger isoform 3 (NHE3) can play a role in some forms of hypertension. Increased NHE3 activity in models of diabetes mellitus may explain, in part, the enhanced salt retention observed in patients with diabetic kidney disease. 3. The NHE3 also plays a role in receptor-mediated albumin uptake in the proximal tubule. The uptake of albumin requires the assembly of a macromolecular complex that is thought to include the megalin/cubulin receptor, NHE3, the vacuolar type H+-ATPase (v-H+-ATPase), the Cl- channel CIC-5 and interactions with the actin cytoskeleton. The NHE3 seems to exist in two functionally distinct membrane domains, one involved with Na+ reabsorption and the other involved in albumin uptake. 4. The present review focuses on the evidence derived from in vivo studies, as well as complementary studies in cell culture models, for a dual role of NHE3 in both Na+ retention and albumin uptake. We suggest a possible mechanism by which disruption of the proximal tubule albumin uptake mechanism in diabetes mellitus may lead to both increased Na+ retention and proteinuria.