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.

(Pro)Renin receptor mediates obesity-induced antinatriuresis and elevated blood pressure via upregulation of the renal epithelial sodium channel

“…It is well established that the PI3K/Akt/mTOR pathway is capable of activating SGK-1, the primary regulator of α-ENaC. [ 32 , 33 ] We have also previously shown that PRR is capable of activating the PI3K/Akt/mTOR pathway under high glucose conditions. [ 34 ] In the previously mentioned study by Ramkumar et al, prorenin stimulated α-ENaC expression in a PRR dependent manner and this was prevented by inhibition of Akt.…”

The Fundamental Role of Bicarbonate Transporters and Associated Carbonic Anhydrase Enzymes in Maintaining Ion and pH Homeostasis in Non-Secretory Organs

“…Recently, kinase-mediated transporter regulation was revealed in the renal system. Renal tubular transport and reabsorption of water and electrolytes are regulated by two kinases, serine/threonine kinase Akt and serum-/glucocorticoid-inducible kinase 1 (SGK1), increasing Na + reabsorption [19]. Signaling pathways involving the phosphorylation of Akt enhance activities of NBCe1, ENaC, and Na + -Cl − cotransporter (NCC), and those involving SGK1 promote NHE3 activation, encouraging reabsorption of Na + .…”

“…Signaling pathways involving the phosphorylation of Akt enhance activities of NBCe1, ENaC, and Na + -Cl − cotransporter (NCC), and those involving SGK1 promote NHE3 activation, encouraging reabsorption of Na + . SGK1, furthermore, increases K + secretion via the renal outer medullary potassium channel (ROMK) [19]. Major modulation of electrolyte transport occurs in the renal and exocrine systems, including salivary glands and pancreatic glands, and has already been extensively discussed [5,20].…”

Effects of phospho- and calciotropic hormones on electrolyte transport in the proximal tubule

“…This raises the possibility that there is molecular crosstalk between the PTH and FGF23 signalling pathways 4 , 163 . Although PKA and PKC seem to be the predominant signalling mechanisms for PTH, they also activate the MAPK pathway, which is activated by FGF23 binding the FGFR 160 , 164 , 165 . Interestingly, the downstream effects of PTH (that is, internalization of NaPi-IIa) were only partially abolished by PKA and PKC inhibition, but inhibition of MAPK completely abolished NaPi-IIa internalization 142 .…”