Tissue-specific Deletion of Collectrin in the Proximal Tubular Epithelium Increases Arterial Pressure and Augments Salt-sensitivity
Medicine and Health Sciences
Background: Collectrin (Tmem27) is a key regulator of blood pressure (BP) and modulator of the bioavailability of nitric oxide (NO) and superoxide. It is highly expressed in the kidney in the proximal tubule (PT), collecting duct, and throughout the vascular endothelium. We reported that collectrin plays a critical role as a chaperone for the reabsorption of all amino acids (AAs) in the PT, and for the uptake of the cationic AA L-arginine (L-Arg) in endothelial cells. Global collectrin knockout (Tmem27Y/-) mice display baseline hypertension (HTN), augmented salt-sensitive hypertension (SSH), and decreased renal blood flow.
Objective and Methods: To determine the PT-specific effect of collectrin on BP homeostasis and salt sensitivity, we used the Cre-loxP approach and PEPCK-Cre to generate a mouse line lacking collectrin specifically in the PT-- PEPCK-Cre+Tmem27Y/Flox mice. PEPCK-Cre-Tmem27Y/Flox mice were used as control. Radiotelemetry was used to measure BP for 2 weeks at baseline and 2 weeks on high salt diet (HSD). Renal blood flow at baseline and on HSD was measured using contrast enhanced ultrasound in the same mice.
Results: Successful deletion of collectrin in the PT was confirmed by assessing mRNA levels using real-time RT-PCR, immunohistochemistry staining of renal tissues using anti-collectrin antibody, and quantitation of protein from kidney cortex by Western analysis. Compared to control PEPCK-Cre-Tmem27Y/Flox mice (n=6), PEPCK-Cre+Tmem27Y/Flox mice (n=6) displayed significantly higher systolic BP (SBP) at baseline (120.0 ± 2.5 vs 131.6 ± 2.9 mm Hg; p = 0.014) and after HSD (135.3 ± 2.6 vs 151.5 ± 5.2 mm Hg; p = 0.019). Renal blood flow was not different between groups, at baseline nor after HSD.
Conclusion: Collectrin in the PT plays an important role in blood pressure homeostasis and response to sodium intake, independent of renal blood flow. Increasing proximal tubular collectrin activity may be a novel therapeutic strategy for the treatment of hypertension and salt-sensitivity.
Sylvia Cechova, Pei-Lun Chu, Joseph C. Gigliotti, Fan Chan, and Thu H Lee, Tissue-specific Deletion of Collectrin in the Proximal Tubular Epithelium Increases Arterial Pressure and Augments Salt-sensitivity, Hypertension, Volume 70, Supplemental Issue 1, September 2017, https://www.ahajournals.org/doi/abs/10.1161/hyp.70.suppl_1.101