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. 2017 Aug 1;313(2):F505-F513.
doi: 10.1152/ajprenal.00087.2017. Epub 2017 May 31.

Gender difference in kidney electrolyte transport. I. Role of AT1a receptor in thiazide-sensitive Na+-Cl- cotransporter activity and expression in male and female mice

Jing Li  1   2 , Ryo Hatano  1 , Shuhua Xu  1 , Laxiang Wan  1 , Lei Yang  3 , Alan M Weinstein  3 , Lawrence Palmer  3 , Tong Wang  4
Affiliations

Gender difference in kidney electrolyte transport. I. Role of AT1a receptor in thiazide-sensitive Na+-Cl- cotransporter activity and expression in male and female mice

Jing Li et al. Am J Physiol Renal Physiol. .

Erratum in

  • Corrigendum.
    [No authors listed] [No authors listed] Am J Physiol Renal Physiol. 2018 Sep 1;315(3):F746. doi: 10.1152/ajprenal-zh2-8577-corr.2018. Am J Physiol Renal Physiol. 2018. PMID: 30444663 Free PMC article. No abstract available.

Abstract

We studied gender differences in Na+-Cl- cotransporter (NCC) activity and expression in wild-type (WT) and AT1a receptor knockout (KO) mice. In renal clearance experiments, urine volume (UV), glomerular filtration rate, absolute Na+ (ENa) and K+ (EK), and fractional Na+ (FENa) and K+ excretion were measured and compared at peak changes after bolus intravenous injection of hydrochlorothiazide (HCTZ; 30 mg/kg). In WT, females responded more strongly than males to HCTZ, with larger fractional increases of UV (7.8- vs. 3.4-fold), ENa (11.7- vs. 5.7-fold), FENa (7.9- vs. 4.9-fold), and EK (2.8- vs. 1.4-fold). In contrast, there were no gender differences in the responses to the diuretic in KO mice; HCTZ produced greater effects on male KO than on WT but similar effects on females. In WT, total (tNCC) and phosphorylated (pNCC) NCC protein expressions were 1.8- and 4.6-fold higher in females compared with males (P < 0.05), consistent with the larger response to HCTZ. In KO mice, tNCC and pNCC increased significantly in males to levels not different from those in females. There were no gender differences in the expression of the Na+/H+ exchanger (NHE3) in WT; NHE3 protein decreased to similar extents in male and female KO animals, suggesting AT1a-mediated NHE3 expression in proximal tubules. The resulting increase in delivery of NaCl to the distal nephron may underlie increased NCC expression and activity in mice lacking the AT1a receptor.

Keywords: angiotensin II; angiotensin type 1a receptor; gender differences; knockout; sodium-chloride cotransporter; urinary sodium and potassium excretion; wild-type.

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Figures

Fig. 1.
Fig. 1.
Time-dependent effects of hydrochlorothiazide (HCTZ) on urine volume (UV, A), glomerular filtration rate (GFR, B), absolute Na+ excretion (ENa, C), and absolute K+ excretion (EK, D) in male (blue) and female (red) wild-type (WT) and knockout (KO) mice. HCTZ (30 mg/kg) was given by bolus iv injection as indicated by arrows. n = 6 Animals in each group. P < 0.05 between gender (*) and WT and KO (#).
Fig. 2.
Fig. 2.
Comparison of fractional increases of UV, ENa, fractional excretion of Na+ (FENa), EK, and fractional excretion of K+ (FEK) at the peak effect of HCTZ (30-min iv injection) between WT and angiotensin type 1a (AT1a) KO male and female mice. Data are expressed as fold changes from baseline. A: male vs. female WT mice. B: male vs. female KO mice. *P < 0.05, significant difference between males and females.
Fig. 3.
Fig. 3.
Comparison of fractional increase of UV, ENa, FENa, EK, and FEK at the peak effect of HCTZ between male and female WT and AT1a KO mice. A: WT vs. AT1a KO male mice. B: WT vs. AT1a KO female mice. #Significant difference between WT and AT1a KO mice (P < 0.05).
Fig. 4.
Fig. 4.
Na+-Cl− cotransporter (NCC) expression in WT and AT1a KO male and female mice kidneys. Total and phosphorylated NCC protein expression in WT and AT1a KO male and female mouse kidneys. A: representative Western blots for total (tNCC) and phosphorylated (pNCC) protein expression. tNCC and pNCC with 3 samples in each group loaded in the same blot. β-Actin expression served as a loading control. B and C: densitometric analysis of tNCC (B) and pNCC (C) expression, represented as the NCC-to-β-actin ratio (n = 4 in each group). D: NCC mRNA expression measured by Q-PCR using whole kidney preparations. P < 0.05, significant difference between male and female (*) and WT and AT1a KO (#).
Fig. 5.
Fig. 5.
Na+/H+ exchanger (NHE3) expression in WT and AT1a KO male and female mice kidneys. A: representative blot for NHE3 protein with 3 samples for each group in the same blot. B: densitometric analysis of NHE3 protein expression represented as the NHE3/β-actin ratio (n = 4 in each group). C: reduction of NHE3 abundance in AT1a KO mice kidneys. D: NHE3 mRNA expression measured by Q-PCR using kidney cortex preparations. #P < 0.05, significant difference between WT and AT1a KO mice kidneys.
Fig. 6.
Fig. 6.
With-no-lysine kinase (WNK4) and phosphorylated (p)-sterile20-related proline-alanine-rich kinase (SPAK)/oxidative stress response kinase1 (OSR1) expression in male and female WT and AT1a KO mice kidneys. A: representative blot for WNK4 and pSPAK/OSR1 protein with 3 samples for each group. B: densitometric analysis of WNK4 and pSPAK/OSR1 protein expression represented as the WNK4/β-actin ratio and pSPAK/OSR1/β-actin ratio (n = 3 in each group). P < 0.05, significant difference between males and females (*) and WT and AT1a KO (#).
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