Impact of High K Intake on Thiazide‐Sensitive Cation Excretion in Male and Female Wild‐type and AT1a Receptor Knockout Mice
Authors: Li Jing , Xu Shuhua , Wang Claire J , Weinstein Alan M , Palmer Lawrence , Wang Tong 
Published: June 2021

Proximal tubule Na reabsorption is a critical determinant of both fluid flow and Na+ delivery to the distal nephron. Beyond that, perturbation of transport by the thiazide‐sensitive Na‐Cl co‐transporter (NCC), within the apical membrane of distal tubule, alters Na+ availability to the Ksecretory machinery of the connecting segment and collecting duct. Potassium intake blunts both proximal Na+ reabsorption via effects on the Na/H‐exchanger (NHE3) and also distal Na+ reabsorption via decreased NCC expression and function. Angiotensin II (Ang II) also impacts both proximal and distal nephron segments, mainly through the AT1a receptor, but its effect is to enhance Na+ reabsorption. Previously we reported that higher NCC expression and activity in female wild‐type (WT) mice, and these gender‐specific differences were absent in AT1aknockout (KO) mice. We have now studied the gender differences in response to high K (HK) intake in WT and AT1a KO mice. In the current work, renal clearance experiments were performed to examine NCC activity on mice fed with control (CK) and HK (5% KCl, 7 days) diets. Hydrochlorothiazide (HCTZ, 30mg/kg iv)‐induced changes in urine volume (UV), glomerular filtration rate (GFR), absolute (ENa, EK) and fractional (FENa, FEK) excretion were measured and compared between male and female WT and AT1a KO mice. HK induced changes in NCC and Na/H‐exchanger isoform 3 (NHE3) expressions were examined by Western blotting. In WT animals, under control diet, HCTZ‐induced cation excretion is greater in females, than in males (ENa+EK was 7.2±1.1 vs. 3.5±0.6 μEq/min/100gBW, P<0.05). This reflects a larger increase in Na+ excretion, as there is little gender difference in HCTZ‐induced K+ excretion (EK/ENa+EK was 20±2 in female and 28±3% in male, P>0.05). Under HK diet, the gender difference in HCTZ‐induced cation excretion is reduced (ENa+EK was 7.0±0.7 in female and 5.2±0.3 μEq/min/100gBW in male P<0.05) accompanied by a larger increment in K+ excretion in males (EK/ENa+EK was 57±5 in male and 36±4% in female P<0.05). With AT1a KO, male mice tend to resemble female mice, with respect to both HCTZ‐induced Na+ and K+ excretion. In turn, the female KO mice are similar to their WT controls. Both NCC and NHE3 transporter abundance were significantly reduced by HK in all groups of mice. In summary, compared with female mice, males appear to rely on greater proximal tubule Na+ reabsorption, showing reduced thiazide‐dependent Na+ excretion. Under control conditions, comparable HCTZ‐dependent K+ excretion by WT males and females – despite reduced Na+ excretion in males ‐ suggests greater sensitivity of K+ secretion to changes in Na+ delivery in the males. HK diet likely increases distal Na+ delivery in both genders, so that HCTZ‐dependent cation excretion is maintained despite reduced NCC abundance. In males, a larger fraction of Na+ escaping the DCT is exchanged for K+, leading to less Na+ excretion and greater K+ excretion than in females. In AT1a KO mice, gender differences in thiazide effect are largely erased, suggesting a role for Ang II in modulating these processes.Support or Funding InformationNIH/NIDDK, RO1 DK099284 and P01 DK 17433This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.