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NCC) Causes Severe Salt Wasting, Volume Depletion, and Renal Failure

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NCC) Causes Severe Salt Wasting, Volume Depletion, and Renal Failure Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure Manoocher Soleimania,b,c,1, Sharon Baronea,b,c, Jie Xua,b,c, Gary E. Shulld, Faraz Siddiquib, Kamyar Zahedia,b,c, and Hassane Amlalb,c aResearch Services, Veterans Affairs Medical Center, Cincinnati, OH 45202; and Departments of bMedicine and dMolecular Genetics, Biochemistry, and Microbiology, and cCenter on Genetics of Transport and Epithelial Biology, University of Cincinnati, Cincinnati, OH 45267 Edited by Richard P. Lifton, Yale University School of Medicine, New Haven, CT, and approved July 2, 2012 (received for review February 15, 2012) The Na-Cl cotransporter (NCC), which is the target of inhibition by with thiazide, can be an effective regimen for patients with fluid thiazides, is located in close proximity to the chloride-absorbing overload, such as congestive heart failure, nephrotic syndrome, transporter pendrin in the kidney distal nephron. Single deletion diuretic resistance, or advanced chronic kidney disease. of pendrin or NCC does not cause salt wasting or excessive diuresis under basal conditions, raising the possibility that these trans- Results porters are predominantly active during salt depletion or in re- Generation of Pendrin/NCC Double KO Mice. The double NCC/ sponse to excess aldosterone. We hypothesized that pendrin and pendrin KO mice were generated by crossing mice with single NCC compensate for loss of function of the other under basal con- deletion of pendrin or NCC with each other. Fig. 1 A and B ditions, thereby masking the role that each plays in salt absorption. demonstrates the generation of double NCC/pendrin KO mice, fi To test our hypothesis, we generated pendrin/NCC double knock- as veri ed by tail genotyping and Northern hybridization. Fig. out (KO) mice by crossing pendrin KO mice with NCC KO mice. 1C shows that 8-wk-old double KO mice are smaller than either single KOs or WT animals (Fig. 1C), with the average body Pendrin/NCC double KO mice displayed severe salt wasting and ∼ sharp increase in urine output under basal conditions. As a result, weight being 40% lower in age-matched double KO mice vs. WT or single KO mice (Fig. 1D)(P < 0.01; n = 5 in each group). animals developed profound volume depletion, renal failure, and Table 1 depicts body weights of WT and double KO mice at the metabolic alkalosis without hypokalemia, which were all corrected time of weaning (end of 3 wk) and at 8 wk of age. The double KO with salt replacement. We propose that the combined inhibition of mice were smaller at 3 wk and remained small at 8 wk of age. pendrin and NCC can provide a strong diuretic regimen without fl The failure to thrive was evident in both sexes. The double KO causing hypokalemia for patients with uid overload, including mice were born in the expected Mendelian distribution. Double patients with congestive heart failure, nephrotic syndrome, di- KO mice survive and live for at least 6 mo, with comparable uretic resistance, or generalized edema. survival rates to those in WT or single KO mice. (Longer-term survival analysis has not been performed.) diuretics | kidney tubules | nephrogenic diabetes insipidus Pendrin/NCC Double KO Mice Have Profound Renal Water and Salt he thiazide-sensitive Na-Cl cotransporter (NCC) (SLC12A3) Wasting. Animals were placed in metabolic cages, and, after ac- − − Tand the Cl /HCO3 exchanger pendrin (SLC26A4) are ex- clamation for 2 d, balanced studies (daily food intake, water in- pressed on apical membranes of distal cortical nephron segments take, urine volume, and body weight) were performed for 4 and mediate salt absorption, with pendrin working in tandem consecutive days. Results in Fig. 2 depict the collections on day 3, with the epithelial Na channel and NCC working by itself (1–6). which is representative of daily experiments, and demonstrate the Pendrin is expressed on the apical membrane of intercalated presence of profound polyuria (increased urine output), along cells in late distal convoluted tubule (DCT), connecting tubule with polydipsia (increased water intake), in double pendrin/NCC (CNT), and the cortical collecting duct (CCD) (7–9). The thia- KO mice but not in single KO mice (Fig. 2 A and B). Fig. 2C zide-sensitive NCC is primarily expressed on the apical mem- demonstrates that urine osmolality is reduced by ∼70% in double brane of DCT cells (10, 11). KO mice vs. the other genotypes. Fig. 2D shows sharp increases in Single deletion of pendrin or NCC does not cause salt wasting sodium and chloride excretion in double pendrin/NCC KO mice. or excessive diuresis under basal conditions (5, 12–15). Indeed, Double KO mice were eating normally; however, when adjusted even a mild degree of salt wasting has not been demonstrated in for body weights, they showed increased food intake vs. WT mice these two genetically engineered mouse models at steady state. (0.163 and 0.207 g food intake/g of body weight in WT and double Kidney functions, including sodium and chloride excretion, urine KO, respectively; P < 0.05, n = 5). Food consumption in single output, and blood urea nitrogen (BUN) levels in mutant mice KO mice (pendrin or NCC) was comparable to WT mice. are comparable to wild-type (WT) animals (12–15). Both pen- drin KO and NCC KO mice, however, show signs of volume Pendrin/NCC Double KO Mice Have Severe Volume Depletion, Renal depletion or develop hypotension during salt restriction (12, 14). Failure, and Metabolic Alkalosis. To determine whether excessive These findings have led investigators to conclude that pendrin salt wasting causes volume depletion in double KO mice, we and NCC are predominantly active during salt depletion (and or in response to increased aldosterone levels), and their contri- bution to salt reabsorption at baseline conditions is small. Author contributions: M.S. and H.A. designed research; M.S., S.B., J.X., F.S., K.Z., and H.A. We hypothesized that NCC and pendrin may compensate for performed research; G.E.S. contributed new reagents/analytic tools; M.S. and H.A. ana- loss of the other under basal conditions, thereby masking the role lyzed data; and M.S. wrote the paper. that each plays in salt reabsorption. To test this hypothesis, we The authors declare no conflict of interest. generated double knockout of pendrin and NCC mice by crossing This article is a PNAS Direct Submission. animals with single deletion for NCC and pendrin. The double KO Freely available online through the PNAS open access option. mice show significant salt and fluid wasting, along with volume 1To whom correspondence should be addressed. E-mail: [email protected]. depletion and renal failure under baseline conditions. We propose This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. that pendrin could be a target for a diuretic that, in conjunction 1073/pnas.1202671109/-/DCSupplemental. 13368–13373 | PNAS | August 14, 2012 | vol. 109 | no. 33 www.pnas.org/cgi/doi/10.1073/pnas.1202671109 Downloaded by guest on September 30, 2021 examined the kidney expression of renin in WT and mutant mice. As shown in Fig. 3A (Upper gels), mRNA expression and protein abundance of renin robustly increased in kidneys of double KO mice relative to single KO or WT mice, with en- hanced mRNA expression and protein abundance by ∼7-fold (P < 0.0001 vs. WT; n = 4) and >10-fold (P < 0.001 vs. WT; n = 5), respectively. These results indicate that the double KO mice are in a state of severe volume depletion. To determine whether salt wasting (Fig. 2) and the subsequent volume depletion (Fig. 3A) impair the kidney function, BUN levels were measured in WT and mutant mice. Results demon- strated a sharp increase in BUN levels in double KO mice rel- ative to other genotypes, consistent with significant prerenal failure (Fig. 3B), which signifies impaired kidney function sub- sequent to decreased perfusion as a result of volume depletion. Double KO animals have normal serum sodium and potassium concentrations (Table 2). To ascertain the impact of severe volume depletion and the subsequent renal failure on acid base balance, systemic acid base parameters in various genotypes were examined (Experi- mental Procedures). As indicated, double pendrin/NCC KO mice have profound metabolic alkalosis vs. WT mice, as determined by elevated serum bicarbonate and arterial pH (Fig. 3C; P < 0.01 vs. WT mice). Mice with NCC deletion have normal serum bicarbonate levels, and mice with pendrin deletion demon- strate mild elevation in serum bicarbonate (12, 15). Blood pressure measurement by the computerized tail cuff method indicated that double KO mice are hypotensive (Fig. 3D; P < 0.01 vs. WT). MEDICAL SCIENCES Effect of Salt Replacement on Volume Depletion, Renal Failure, and Metabolic Alkalosis in Pendrin/NCC Double KO Mice. To ascertain the role of volume depletion in the pathogenesis of renal failure and metabolic alkalosis, double pendrin/NCC KO and WT mice were placed on high-salt (7%) diet for 7 d. Fig. 4A (Left and Right) demonstrates that the mRNA expression levels of renin de- creased by ∼90% in kidneys of double KO mice on high-salt intake relative to normal diet. The above results demonstrate that salt replacement significantly improves the vascular volume depletion in double KO mice. Fig. 4B shows that BUN levels, although mildly higher in double KO vs. WT mice, are signifi- cantly decreased in double KO mice on high-salt diet relative to normal diet (comparison vs. Fig. 3B). Fig. 4C indicates significant improvement in the severity of metabolic alkalosis, as verified by a sharp reduction in serum bicarbonate levels in double KO mice on high-salt vs.
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