Differential regulation of Na⁺transporters along nephron during ANG II-dependent hypertension: distal stimulation counteracted by proximal inhibition

Abstract

During angiotensin II (ANG II)-dependent hypertension, ANG II stimulates, while hypertension inhibits, Na(+) transporter activity to balance Na(+) output to input. This study tests the hypothesis that ANG II infusion activates Na(+) transporters in the distal nephron while inhibiting transporters along the proximal nephron. Male Sprague-Dawley rats were infused with ANG II (400 ng·kg(-1)·min(-1)) or vehicle for 2 wk. Kidneys were dissected (cortex vs. medulla) or fixed for immunohistochemistry (IHC). ANG II increased mean arterial pressure by 40 mmHg, urine Na(+) by 1.67-fold, and urine volume by 3-fold, evidence for hypertension and pressure natriuresis. Na(+) transporters' abundance and activation [assessed by phosphorylation (-P) or proteolytic cleavage] were measured by immunoblot. During ANG II infusion Na(+)/H(+) exchanger 3 (NHE3) abundance decreased in both cortex and medulla; Na-K-2Cl cotransporter 2 (NKCC2) decreased in medullary thick ascending loop of Henle (TALH) and increased, along with NKCC2-P, in cortical TALH; Na-Cl cotransporter (NCC) and NCC-P increased in the distal convoluted tubule; and epithelial Na(+) channel subunits and their cleaved forms were increased in both cortex and medulla. Like NKCC2, STE20/SPS1-related proline alanine-rich kinase (SPAK) and SPAK-P were decreased in medulla and increased in cortex. By IHC, during ANG II NHE3 remained localized to proximal tubule microvilli at lower abundance, and the differential regulation of NKCC2 and NKCC2-P in cortex versus medulla was evident. In summary, ANG II infusion increases Na(+) transporter abundance and activation from cortical TALH to medullary collecting duct while the hypertension drives a natriuresis response evident as decreased Na(+) transporter abundance and activation from proximal tubule through medullary TALH.

Role of caveolin 1 in AT1a receptor-mediated uptake of angiotensin II in the proximal tubule of the kidney

“…Genetic deletion of CAV-1 impairs NOS/NO trafficking and signaling and, thus, the pressure natriuresis response. Second, ANG II has biphasic effects on the expression and activity of NHE3 in the proximal tubule of the kidney, with stimulation by nonpressor doses and inhibition by pressor doses of ANG II (25,32). Furthermore, it has been shown that the epithelial Na ϩ channel is enriched in caveolin-rich lipid rafts and that pharmacological disruption of lipid raft formation decreases the activity of epithelial Na ϩ channels (16).…”

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

“…Recently significant insights into how the NHERFs and ezrin affect NHE3 activity, the mechanisms underlying angiotensin II mediated activation of the exchanger, the role of SGK signalling and NHE3 lipid interactions on activity have been made [1,149,30,8,9,184,112,68,117,64].…”

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

“…Although this review focused on NCC, sodium excretion by the kidney depends on many other sodium transporters, including NHE3, NKCC2, ENaC, and pendrin. Stimuli that activate NCC, sometimes also activate these other transporters, but an opposite, compensatory response may also occur [38,84,99]. In conclusion, the role of NCC in normal physiology and in the pathophysiology of hypertension is expanding and will 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 20 likely continue to do so in coming years.…”