Insulin's impact on renal sodium transport and blood pressure in health, obesity, and diabetes

Abstract

Insulin has been shown to have antinatriuretic actions in humans and animal models. Moreover, endogenous hyperinsulinemia and insulin infusion have been correlated to increased blood pressure in some models. In this review, we present the current state of understanding with regard to the regulation of the major renal sodium transporters by insulin in the kidney. Several groups, using primarily cell culture, have demonstrated that insulin can directly increase activity of the epithelial sodium channel, the sodium-phosphate cotransporter, the sodium-hydrogen exchanger type III, and Na-K-ATPase. We and others have demonstrated alterations in the expression at the protein level of many of these same proteins with insulin infusion or in hyperinsulinemic models. We also discuss how this regulation is perturbed in type I and type II diabetes mellitus. Finally, we discuss a potential role for regulation of insulin receptor signaling in the kidney in contributing to sodium balance and blood pressure. insulin resistance; ENaC; Zucker rats; streptozotocin Overview INSULIN HAS BEEN DEMONSTRATED to increase sodium reabsorption in the proximal tubule (9), the thick ascending limb (78, 102), and the distal tubule including the collecting duct (54, 144), using micropuncture and perfused tubule approaches. Over 10 years ago, Sechi (127), Butlen (30), and colleagues using I 125 -labeled insulin demonstrated binding sites in multiple cell types along the renal tubular epithelium. However, because the kidney expresses other receptors similar to the classic insulin receptor (IR), including the insulin growth factor receptor (IGF) and the IR-related receptor (IRR), the precise nature of the "receptor" that labeled insulin was binding to was not absolutely certain. Nonetheless, more recent studies showed mRNA expression of the classic IR in whole homogenates of the kidney (31, 32,130,132), and our group (150) has recently found IR expression at the protein level using immunoblotting and immunohistochemistry in the proximal tubule, thick ascending limb, and collecting duct. In this review, we discuss studies that have investigated the regulation of the major renal sodium transporters in the kidney by insulin. In addition, we examine how this regulation is altered in insulin resistance, which is a hyperinsulinemic state, as well as in type I and type II diabetes. We also discuss what is known about the regulation of the IR in the kidney, how it is affected by insulin resistance and/or diabetes, and how this might ultimately affect sodium balance and blood pressure.

Insulin activates epithelial sodium channel (ENaC) via phosphoinositide 3-kinase in mammalian taste receptor cells

“…This intracellular solution helped to eliminate any inward Cl Ϫ or K ϩ current since the E Cl and E K were approximately Ϫ80 mV. In most TRCs, insulin increased inward Na ϩ currents, consistent with previous studies in other transporting epithelia that showed that the ability of insulin to enhance Na ϩ movement is through the activation of ENaC (38,44). To determine whether the insulin-enhanced responses we recorded were attributable to ENaC, we recorded insulininduced responses in the presence or absence of amiloride (30 M) and/or benzamil (10 M).…”

“…3). Similar results in kidney epithelia studies have also suggested that insulin contributes to Na ϩ movement via ENaC (43,44). Insulin-mediated Na ϩ reabsorption occurs through activation of PI3-kinase.…”

“…Autophosphorylation of IR elicits a number of downstream events including phosphorylation of IRS and PI3-kinase (3,44). To verify the expression of IR, insulin receptor substrate 1 (IRS-1), and insulin receptor substrate 2 (IRS-2) in mouse taste buds, a series of RT-PCR assays were performed using total RNA isolated from fungiform, foliate, and circumvallate taste buds.…”

The WNK Kinase Network Regulating Sodium, Potassium, and Blood Pressure

“…90 Hyperinsulinemia is a prominent feature of insulin resistance, diabetes mellitus, and obesity. Insulin receptors are expressed in the proximal tubule, DCT, and CD.…”

“…Insulin receptors are expressed in the proximal tubule, DCT, and CD. 90 Song et al 91 showed that the rise in BP in rats on chronic insulin treatment is likely caused by enhanced sodium reabsorption by NCC and ENaC, because treatment with hydrochlorothiazide and amiloride results in increased natriuresis. Interestingly, insulin also reduces renal cortical WNK4 expression, which contributes to activation of NCC and ENaC.…”