Insulin activates Na⁺/H⁺exchanger 3: biphasic response and glucocorticoid dependence

Abstract

Insulin is an important regulator of renal salt and water excretion, and hyperinsulinemia has been implicated to play a role in hypertension. One of the target proteins of insulin action in the kidney is Na+/H+ exchanger 3 (NHE3), a principal Na+ transporter responsible for salt absorption in the mammalian proximal tubule. The molecular mechanisms involved in activation of NHE3 by insulin have not been studied so far. In opossum kidney (OK) cells, insulin increased Na+/H+exchange activity in a time- and concentration-dependent manner. This effect is due to activation of NHE3 as it persisted after pharmacological inhibition of NHE1 and NHE2. In the early phase of stimulation (2–12 h), NHE3 activity was increased without changes in NHE3 protein and mRNA. At 24 h, enhanced NHE3 activity was accompanied by an increase in total and cell surface NHE3 protein and NHE3 mRNA abundance. All the effects of insulin on NHE3 activity, protein, and mRNA were amplified in the presence of hydrocortisone. These results suggest that insulin stimulates renal tubular NHE3 activity via a biphasic mechanism involving posttranslational factors and an increase in NHE3 gene expression and the effects are dependent on the permissive action of hydrocortisone.

Low Urine pH

“…Renal ammonium production and excretion are regulated by the ambient acid-base environment. Insulin influences these two processes (32,33), and mechanisms of acid-base homeostasis may be altered in a state of insulin resistance (13). Consistent with this possibility, participants with the MS in our cohort exhibited lower ammonium excretion per NAE (NH 4 ϩ /NAE).…”

Metabolic syndrome and renal sodium handling in three ethnic groups living in England

“…Although insulin is thought primarily to affect distal tubular sodium re-absorption [21,22,23,24], there is evidence of a direct insulin action on proximal tubular sodium re-absorption [25,26]; moreover, insulin receptors have been found in the proximal tubule of different species [27,28,29]. Finally, insulin increases the expression and the activity of sodium-hydrogen exchange isoform 3, which mediates more than 60% of the sodium re-absorption at the proximal tubule [30].…”

Obesity and Kidney Disease: Hidden Consequences of the Epidemic

“…The insulin resistance characteristic of obesity may also predispose to nephrolithiasis 51 through its impact on tubular Na-H exchanger 52 and ammoniagenesis, 53 and the promotion of an acidic milieu. 54 Complicating the picture is the fact that some weight loss therapies result in a worsening, rather than an improvement in the risk for kidney stone formation; e.g.…”