Roles of Akt and SGK1 in the Regulation of Renal Tubular Transport

Abstract

A serine/threonine kinase Akt is a key mediator in various signaling pathways including regulation of renal tubular transport. In proximal tubules, Akt mediates insulin signaling via insulin receptor substrate 2 (IRS2) and stimulates sodium-bicarbonate cotransporter (NBCe1), resulting in increased sodium reabsorption. In insulin resistance, the IRS2 in kidney cortex is exceptionally preserved and may mediate the stimulatory effect of insulin on NBCe1 to cause hypertension in diabetes via sodium retention. Likewise, in distal convoluted tubules and cortical collecting ducts, insulin-induced Akt phosphorylation mediates several hormonal signals to enhance sodium-chloride cotransporter (NCC) and epithelial sodium channel (ENaC) activities, resulting in increased sodium reabsorption. Serum- and glucocorticoid-inducible kinase 1 (SGK1) mediates aldosterone signaling. Insulin can stimulate SGK1 to exert various effects on renal transporters. In renal cortical collecting ducts, SGK1 regulates the expression level of ENaC through inhibition of its degradation. In addition, SGK1 and Akt cooperatively regulate potassium secretion by renal outer medullary potassium channel (ROMK). Moreover, sodium-proton exchanger 3 (NHE3) in proximal tubules is possibly activated by SGK1. This review focuses on recent advances in understanding of the roles of Akt and SGK1 in the regulation of renal tubular transport.

Figure 1

Schematic structure of Akt1. Akt1 has 480 amino acids and it is composed of four domains: the pleckstrin homology domain, the helix domain, the kinase domain, and the regulatory domain. The kinase and the regulatory domains have phosphorylation sites at Thr308 and Ser473, respectively. Phosphorylation of these sites induces Akt1 activation.

Figure 2

Insulin-mediated Akt signaling. Insulin binding to insulin receptor induces Akt activation through IRS/PI3K pathway. mTORC2 also activates Akt. Activated Akt regulates various biological functions such as cell survival and proliferation, protein synthesis, glycogen synthesis, sodium transport, and glucose uptake through translocation of GLUT4. IR: insulin receptor, IRS: insulin receptor substrate, PI3K: phosphatidylinositol 3-kinase, PDK1: phosphoinositide-dependent protein kinase 1, and mTORC2: mammalian target of rapamycin complex 2.

Figure 3

Effects of insulin on PT sodium transport. Insulin stimulates NBCe1 and NHE3 via IRS2/PI3K/Akt pathway. PPARγ and SGK1 may be involved in the stimulatory effect on PT sodium transport. NBCe1: sodium-bicarbonate cotransporter 1, NHE3: sodium-proton exchanger 3, PPARγ: peroxisome proliferator-activated receptor gamma, and SGK1: serum- and glucocorticoid-inducible kinase 1.

Figure 4

SGK1-mediated signaling pathway. Aldosterone stimulates SGK1 via mineralocorticoid receptor (MR), while insulin stimulates SGK1 via IRS/PI3K pathway. SGK1 is phosphorylated twofold by PDK1 and PDK2. Activated SGK1 exerts stimulatory effects on sodium transport through ENaC, NCC, and NHE3. Also, SGK1 regulates potassium secretion through ROMK. SGK1: serum- and glucocorticoid-inducible kinase 1, IRS: insulin receptor substrate, PI3K: phosphatidylinositol 3-kinase, PDK1: phosphoinositide-dependent protein kinase 1, WNK1: with-no-lysine kinase 1, ENaC: epithelial Na⁺ channel, ROMK: renal outer medullary potassium channel, and NHE3: sodium-proton exchanger 3.

Figure 5

Roles of Akt and SGK1 in transport regulation at each nephron segment: Akt and SGK1 modify renal tubular transport by activating or inhibiting several transporters at each nephron segment. Targets and functions of the kinases in proximal tubules, distal convoluted tubules, and cortical collecting ducts are shown in (a), (b), and (c), respectively.