Figure 1. Renal transporter profile reveals region specific transporter regulation during experimental hypertension.

A. Anatomical arrangement of renal cortex and renal medulla in a kidney cross section with adjacent drawing of a single nephron indicating locations of sodium transporters, ENaC and SPAK. Cortical NHE3 and NaPi2 are primarily restricted to the proximal tubules where 2/3 of the filtered load is reabsorbed. Medullary NHE3 is expressed in the S3 portion of the proximal tubule that terminates in the medulla as well as in the thick ascending limb of the loop of Henle. NKCC2 (target of loop diuretics) is expressed in both medulla and cortex all along the thick ascending limb. NCC (target of thiazide diuretics) is localized to the cortical distal convoluted tubule and SPAK (kinase that activates NKCC2 and NCC) is expressed in both cortex and medulla from thick ascending limb through distal convoluted tubules. Epithelial sodium channel (ENaC, target of potassium sparing diuretics) alpha, beta and gamma subunits are expressed in the cortex from late distal convoluted tubule through to principal cells of the cortical collecting duct, as well as in the medullary collecting ducts. B. Effects of AngII infusion into rats (400 ng/kg/min for 14 days) replotted from Nguyen et. al.,²⁸ expressed as protein abundance relative to mean abundance in control untreated rats, defined as 1.0. Definitions: FL = full length form, p = phosphorylated form, cleaved = ENaC subunits cleaved to smaller molecular weight forms associated with channel activation. Summary: Distal nephron NKCC, NCC, SPAK and their phosphorylated forms all increase significantly (NCCpT53 and NCCpS89 also significantly increase 5 and 3 fold, respectively); cortical alpha (a-ENaC) and beta (b-ENaC) as well as cleaved a-ENaC and g-ENaC subunits significantly increase. In contrast, cortical NHE3 and medullary thick limb NHE3, NKCC, NKCCp, sodium pump alpha and beta subunits (a-NKA, b-NKA), SPAK and SPAKp are all significantly depressed in abundance during AngII hypertension. C. Integration of responses to maintain fluid balance: antinatriuretic stimuli including AngII, reactive oxygen species (ROS), cytokines and renal sympathetic nervous system activity (RSNA) can stimulate salt reabsorption (red arrows) increasing effective circulating volume and blood pressure which can suppress salt transporters (blue arrow).