Figure 5.

TRPV4 and SGK1 in the kidney. In healthy nondiabetic individuals, SGK1 is responsible for insertion and retention of ENaCs into the apical cell membrane, promoting ENaC-mediated Na⁺ reabsorption from the lumen of the cortical collecting duct (a). SGK1 also stimulates the Na⁺,K⁺-ATPase on the basolateral membrane. TRPV4 receptors will be activated as a counterregulatory mechanism, initiating a calcium-dependent response, which ensures activation of a regulatory volumes decrease. Through the actions of SGK1 and TRPV4 cell volume homeostasis is maintained. In a patient with diabetes, however, these counter-regulatory mechanisms may become compromised as a consequence of glucose-evoked changes in expression (b). SGK expression is increased in response to high glucose. Similarly, glycosuria may initiate cell shrinkage as water is lost to the lumen. Cell shrinkage is a key trigger for SGK1 activation. This will result in enhanced SGK1 activity, increased [Na⁺]_i, and enhanced osmotic drag, all of which induce cell swelling. Whilst under healthy conditions this will be compensated for by a TRPV4-mediated regulatory cell volume decrease; in high glucose, a loss in the expression of this channel (b) will reduce sensitivity of the cell to deformation at the membrane and [Na⁺]_i will rise.