Loss of Protein Kinase C Alpha Disrupts Mean Arterial Pressure and Diurnal Rhythm

Abstract

The sodium‐chloride cotransporter (NCC) is an essential regulator of sodium transport in the distal convoluted tubule (DCT). As such, functional aberrations will lead to dysregulation of sodium homeostasis and blood pressure. Although this role is well accepted, the mechanisms accounting for increased distal nephron sodium reabsorption is not completely understood. Previously published data from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study revealed that a single nucleotide polymorphism (SNP) in PKC‐α increases sensitivity to thiazide diuretics. To date, it is unknown whether this SNP is a gain or loss of function of PKC‐α. To investigate whether PKC‐α may be altering blood pressure via NCC, PKC‐α KO (PKC KO) and PKC Control (CTL) mice were used to measure blood pressure via radiotelemetry after normal and high salt (HS, 4%) dietary manipulations and Western blot analysis performed using kidney lysates. Using radiotelemetry (DSI) measurements obtained over an active and sleeping time periods, we report a significant decrease in mean arterial pressure (MAP) in the PKC KO mice as compared to control at baseline (111±1.3mmHg vs 120±2.4mmHg, n=12–16, p<0.001). When comparing active vs. sleeping MAP, PKC KO mice had depressed MAP during both time periods, yet blood pressure differences (day vs. night) double during active periods (5.4±1.3mmHg PKC KO vs. 10.9±3.9mmHg PKC CTL, n=6–7). These differences were abolished with HS chow feeding (17.3mmHg PKC KO vs. 16.1mmHg PKC CTRL, n=4). To determine a possible mechanism for this phenomenon, whole kidney lysate was used to assay for total NCC protein. Total NCC protein was significantly increased in PKC KO mice at baseline, and continued during HS chow feeding, as compared to PKC CTL. In addition, PKC KO mice exhibited a diuresis with both normal and HS feeding. Our data suggest that lack of PKC‐α leads to decreased MAPs and diuresis, which may lead to increased total NCC expression to compensate. In addition, PKC KO mice exhibited an aberrant diurnal rhythm, which was recovered with HS diet suggesting that PKC‐α may be necessary to maintain sodium homeostasis.Support or Funding InformationNIDDK085097‐ RSH 2T32DK7656‐21 Emory Renal Division‐BMW