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Abstract: FR-OR076

Connexin40 (Cx40) Knockout Rat Has Impaired Renal Autoregulation

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Cupples, William A., Simon Fraser University, Burnaby, British Columbia, Canada
  • Braam, Branko, University of Alberta, Edmonton, Alberta, Canada
Background

Renal autoregulation is mediated by the generic myogenic response (MR), modulated by the kidney-specific tubuloglomerular feedback (TGF). Recent studies have indicated that TGF acts on a larger scale than individual nephrons and that the well-known synchronization of TGF dynamics operates on macroscopic scales, communicating electrically along the vasculature via gap junction intercellular communication.

Methods

A Wistar Kyoto (WKY) rat lacking Cx40 was made at the Genome Editing Rat Resource Center (https://rgd.mcw.edu/wg/gerrc/). Heterozygous parents produce wild type (WT), heterozygous (HET), and knockout (KO) offspring in Mendelian ratios. In anesthetized rats, surface perfusion of renal cortex in all genotypes was studied by laser speckle contrast imaging (LSCI) in an area 2.75×2.75 mm. ROIs captured blood flow dynamics in star vessels. Synchronization was assessed by phase coherence (PC) between all possible ROI pairs (Scully et al. IEEETBME 2014; 1989-97). Blood pressure (BP) and renal blood flow (RBF) were monitored. Data are reported as mean±SEM. Significance testing was not done because N is not yet sufficient for it to be meaningful.

Results

In WT and HET rats (N = 3 each) BP and RBF were similar (WT: 100±2 mmHg, 6.57±0.56 mL/min; HET: 98±4 mmHg, 6.12±1.84 mL/min) while in KO rats (N = 3) BP appeared higher and RBF lower (123±6 mmHg, 4.52±0.86 mL/min). There was a pronounced gene dosage effect on TGF synchronization. In N=6 WT rats 86±10% of possible connections had statistically significant PC and of those 37±14% had PC >0.6 which is considered to be significant for autoregulation. In N=6 HET rats 95±4% of possible connections were significant and of those 18±10% had PC >0.6. In N=5 KO rats 62±16% were significant and 5±2 had PC >0.6. Renal autoregulation assessed by transfer functions was visibly impaired.

Conclusion

We report a new knockout rat on the normotensive Wistar Kyoto background that lacks Cx40. Wildtype, heterozygote, and Knock-out are bred in Mendelian ratios. As expected from the Cx40 knockout mouse, KO rats appear to be hypertensive, probably due to dis-regulated renin secretion. TGF synchronization is, and autoregulatory effectiveness appears to be, grossly impaired in the absence of Cx40.