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Sodium butyrate ameliorates deoxycorticosterone acetate/salt-induced hypertension and renal damage by inhibiting the MR/SGK1 pathway


Our recent work demonstrates that infusion of sodium butyrate (NaBu) into the renal medulla blunts angiotensin II-induced hypertension and improves renal injury. The present study aimed to test whether oral administration of NaBu attenuates salt-sensitive hypertension in deoxycorticosterone acetate (DOCA)/salt-treated rats. Uninephrectomized male Sprague-Dawley (SD) rats were treated with DOCA pellets (150 mg/rat) plus 1% NaCl drinking water for 2 weeks. Animals received oral administration of NaBu (1 g/kg) or vehicle once per day. Our results showed that NaBu administration significantly attenuated DOCA/salt-increased mean arterial pressure from 156 ± 4 mmHg to 136 ± 1 mmHg. DOCA/salt treatment markedly enhanced renal damage as indicated by an increased ratio of kidney weight/body weight, elevated urinary albumin, extensive fibrosis, and inflammation, whereas kidneys from NaBu-treated rats exhibited a significant reduction in these renal damage responses. Compared to the DOCA/salt group, the DOCA/salt-NaBu group had ~30% less salt water intake and decreased Na+ and Cl- excretion in urine but no alteration in 24-h urine excretion. Mechanistically, NaBu inhibited the protein levels of several sodium transporters stimulated by DOCA/salt in vivo, such as βENaC, γENaC, NCC, and NKCC-2. Further examination showed that NaBu downregulated the expression of mineralocorticoid receptor (MR) and serum and glucocorticoid-dependent protein kinase 1 (SGK1) in DOCA/salt-treated rats or aldosterone-treated human renal tubular duct epithelial cells. These results provide evidence that NaBu may attenuate DOCA/salt-induced hypertension and renal damage by inhibiting the MR/SGK1 pathway.

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  1. 1.

    O’Donnell M, Mente A, Yusuf S. Sodium intake and cardiovascular health. Circ Res. 2015;116:1046–57.

    Google Scholar 

  2. 2.

    Smiljanec K, Lennon SL. Sodium, Hypertension, and the Gut: Does the Gut Microbiota Go Salty? Am J Physiol Heart Circ Physiol. 2019;317:H1173–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Appel LJ, Frohlich ED, Hall JE, Pearson TA, Sacco RL, Seals DR, et al. The importance of population-wide sodium reduction as a means to prevent cardiovascular disease and stroke: a call to action from the American Heart Association. Circulation. 2011;123:1138–43.

    PubMed  Google Scholar 

  4. 4.

    Basting T, Lazartigues E. DOCA-salt hypertension: an update. Curr Hypertens Rep. 2017;19:32.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Gomez-Sanchez EP. DOCA/Salt: much more than a model of hypertension. J Cardiovasc Pharmacol. 2019;74:369–71.

    CAS  PubMed  Google Scholar 

  6. 6.

    Kubacka M, Zadrozna M, Nowak B, Kotanska M, Filipek B, Waszkielewicz AM, et al. Reversal of cardiac, vascular, and renal dysfunction by non-quinazoline alpha1-adrenolytics in DOCA-salt hypertensive rats: a comparison with prazosin, a quinazoline-based alpha1-adrenoceptor antagonist. Hypertens Res. 2019;42:1125–41.

    CAS  PubMed  Google Scholar 

  7. 7.

    Barger AC, Berlin RD, Tulenko JF. Infusion of aldosterone, 9-alpha-fluorohydrocortisone and antidiuretic hormone into the renal artery of normal and adrenalectomized, unanesthetized dogs: effect on electrolyte and water excretion. Endocrinology. 1958;62:804–15.

    CAS  PubMed  Google Scholar 

  8. 8.

    Verrey F, Kraehenbuhl JP, Rossier BC. Aldosterone induces a rapid increase in the rate of Na,K-ATPase gene transcription in cultured kidney cells. Mol Endocrinol. 1989;3:1369–76.

    CAS  PubMed  Google Scholar 

  9. 9.

    May A, Puoti A, Gaeggeler HP, Horisberger JD, Rossier BC. Early effect of aldosterone on the rate of synthesis of the epithelial sodium channel alpha subunit in A6 renal cells. J Am Soc Nephrol. 1997;8:1813–22.

    CAS  PubMed  Google Scholar 

  10. 10.

    Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension. 1986;8:II127–34.

    CAS  PubMed  Google Scholar 

  11. 11.

    Liu L, Gonzalez AA, McCormack M, Seth DM, Kobori H, Navar LG, et al. Increased renin excretion is associated with augmented urinary angiotensin II levels in chronic angiotensin II-infused hypertensive rats. Am J Physiol Ren Physiol. 2011;301:F1195–201.

    CAS  Google Scholar 

  12. 12.

    Funder JW. Aldosterone, hypertension and heart failure: insights from clinical trials. Hypertens Res. 2010;33:872–5.

    CAS  PubMed  Google Scholar 

  13. 13.

    Nishiyama A. Pathophysiological mechanisms of mineralocorticoid receptor-dependent cardiovascular and chronic kidney disease. Hypertens Res. 2019;42:293–300.

    CAS  PubMed  Google Scholar 

  14. 14.

    Nguyen Dinh Cat A, Jaisser F. Extrarenal effects of aldosterone. Curr Opin Nephrol Hypertens. 2012;21:147–56.

    CAS  PubMed  Google Scholar 

  15. 15.

    Terker AS, Ellison DH. Renal mineralocorticoid receptor and electrolyte homeostasis. Am J Physiol Regul Integr Comp Physiol. 2015;309:R1068–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Valinsky WC, Touyz RM, Shrier A. Aldosterone, SGK1, and ion channels in the kidney. Clin Sci (Lond). 2018;132:173–83.

    CAS  Google Scholar 

  17. 17.

    Lou Y, Zhang F, Luo Y, Wang L, Huang S, Jin F. Serum and glucocorticoid regulated kinase 1 in sodium homeostasis. Int J Mol Sci. 2016;17:1307.

    PubMed Central  Google Scholar 

  18. 18.

    Lang F, Stournaras C, Zacharopoulou N, Voelkl J, Alesutan I. Serum- and glucocorticoid-inducible kinase 1 and the response to cell stress. Cell Stress. 2018;3:1–8.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Artunc F, Amann K, Nasir O, Friedrich B, Sandulache D, Jahovic N, et al. Blunted DOCA/high salt induced albuminuria and renal tubulointerstitial damage in gene-targeted mice lacking SGK1. J Mol Med. 2006;84:737–46.

    CAS  PubMed  Google Scholar 

  20. 20.

    Hou J, Speirs HJ, Seckl JR, Brown RW. Sgk1 gene expression in kidney and its regulation by aldosterone: spatio-temporal heterogeneity and quantitative analysis. J Am Soc Nephrol. 2002;13:1190–8.

    CAS  PubMed  Google Scholar 

  21. 21.

    Vallon V, Huang DY, Grahammer F, Wyatt AW, Osswald H, Wulff P, et al. SGK1 as a determinant of kidney function and salt intake in response to mineralocorticoid excess. Am J Physiol Regul Integr Comp Physiol. 2005;289:R395–401.

    CAS  PubMed  Google Scholar 

  22. 22.

    Stevens VA, Saad S, Poronnik P, Fenton-Lee CA, Polhill TS, Pollock CA. The role of SGK-1 in angiotensin II-mediated sodium reabsorption in human proximal tubular cells. Nephrol Dial Transpl. 2008;23:1834–43.

    CAS  Google Scholar 

  23. 23.

    Fejes-Toth G, Frindt G, Naray-Fejes-Toth A, Palmer LG. Epithelial Na+ channel activation and processing in mice lacking SGK1. Am J Physiol Ren Physiol. 2008;294:F1298–305.

    CAS  Google Scholar 

  24. 24.

    Miranda PM, De Palma G, Serkis V, Lu J, Louis-Auguste MP, McCarville JL, et al. High salt diet exacerbates colitis in mice by decreasing Lactobacillus levels and butyrate production. Microbiome. 2018;6:57.

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Juanola O, Ferrusquia-Acosta J, Garcia-Villalba R, Zapater P, Magaz M, Marin A, et al. Circulating levels of butyrate are inversely related to portal hypertension, endotoxemia, and systemic inflammation in patients with cirrhosis. FASEB J. 2019;33:11595–605.

    CAS  PubMed  Google Scholar 

  26. 26.

    Hsu CN, Lu PC, Hou CY, Tain YL. Blood pressure abnormalities associated with gut microbiota-derived short chain fatty acids in children with congenital anomalies of the kidney and urinary tract. J Clin Med. 2019;8:1090.

    CAS  PubMed Central  Google Scholar 

  27. 27.

    Yang T, Magee KL, Colon-Perez LM, Larkin R, Liao YS, Balazic E, et al. Impaired butyrate absorption in the proximal colon, low serum butyrate and diminished central effects of butyrate on blood pressure in spontaneously hypertensive rats. Acta Physiol. 2019;226:e13256.

    Google Scholar 

  28. 28.

    Toral M, Romero M, Rodriguez-Nogales A, Jimenez R, Robles-Vera I, Algieri F, et al. Lactobacillus fermentum Improves Tacrolimus-Induced Hypertension by Restoring Vascular Redox State and Improving eNOS Coupling. Mol Nutr Food Res. 2018;e1800033.

  29. 29.

    Wilck N, Matus MG, Kearney SM, Olesen SW, Forslund K, Bartolomaeus H, et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature. 2017;551:585–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Marques FZ, Nelson E, Chu PY, Horlock D, Fiedler A, Ziemann M, et al. High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice. Circulation 2017;135:964–77.

    CAS  PubMed  Google Scholar 

  31. 31.

    Wang L, Zhu Q, Lu A, Liu X, Zhang L, Xu C, et al. Sodium butyrate suppresses angiotensin II-induced hypertension by inhibition of renal (pro)renin receptor and intrarenal renin-angiotensin system. J Hypertension. 2017;35:1899–908.

    CAS  Google Scholar 

  32. 32.

    Yang T, Rodriguez V, Malphurs WL, Schmidt JT, Ahmari N, Sumners C, et al. Butyrate regulates inflammatory cytokine expression without affecting oxidative respiration in primary astrocytes from spontaneously hypertensive rats. Physiol Rep. 2018;6:e13732.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Zhang L, Deng M, Lu A, Chen Y, Chen Y, Wu C, et al. Sodium butyrate attenuates angiotensin II-induced cardiac hypertrophy by inhibiting COX2/PGE2 pathway via a HDAC5/HDAC6-dependent mechanism. J Cell Mol Med. 2019;23:8139–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Bier A, Braun T, Khasbab R, Di Segni A, Grossman E, Haberman Y, et al. A high salt diet modulates the gut microbiota and short chain fatty acids production in a salt-sensitive hypertension rat model. Nutrients. 2018;10:1154.

    PubMed Central  Google Scholar 

  35. 35.

    Arai K, Morikawa Y, Ubukata N, Tsuruoka H, Homma T. CS-3150, a novel nonsteroidal mineralocorticoid receptor antagonist, shows preventive and therapeutic effects on renal injury in deoxycorticosterone acetate/salt-induced hypertensive rats. J Pharm Exp Ther. 2016;358:548–57.

    CAS  Google Scholar 

  36. 36.

    Arai K, Homma T, Morikawa Y, Ubukata N, Tsuruoka H, Aoki K, et al. Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist. Eur J Pharm. 2015;761:226–34.

    CAS  Google Scholar 

  37. 37.

    Sun X, Zhang B, Hong X, Zhang X, Kong X. Histone deacetylase inhibitor, sodium butyrate, attenuates gentamicin-induced nephrotoxicity by increasing prohibitin protein expression in rats. Eur J Pharmacol. 2013;707:147–54.

    CAS  PubMed  Google Scholar 

  38. 38.

    Kumar P, Gogulamudi VR, Periasamy R, Raghavaraju G, Subramanian U, Pandey KN. Inhibition of HDAC enhances STAT acetylation, blocks NF-kappaB, and suppresses the renal inflammation and fibrosis in Npr1 haplotype male mice. Am J Physiol Ren Physiol. 2017;313:F781–95.

    CAS  Google Scholar 

  39. 39.

    Kumar P, Periyasamy R, Das S, Neerukonda S, Mani I, Pandey KN. All-trans retinoic acid and sodium butyrate enhance natriuretic peptide receptor a gene transcription: role of histone modification. Mol Pharmacol. 2014;85:946–57.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Iyer A, Fenning A, Lim J, Le GT, Reid RC, Halili MA, et al. Antifibrotic activity of an inhibitor of histone deacetylases in DOCA-salt hypertensive rats. Br J Pharm. 2010;159:1408–17.

    CAS  Google Scholar 

  41. 41.

    Bae EH, Kim IJ, Song JH, Choi HS, Kim CS, Eom GH, et al. Renoprotective effect of the histone deacetylase inhibitor CG200745 in DOCA-salt hypertensive rats. Int J Mol Sci. 2019;20:508.

    CAS  PubMed Central  Google Scholar 

  42. 42.

    Guo J, Wang Z, Wu J, Liu M, Li M, Sun Y, et al. Endothelial SIRT6 is vital to prevent hypertension and associated cardiorenal injury through targeting Nkx3.2-GATA5 signaling. Circ Res. 2019;124:1448–61.

    CAS  PubMed  Google Scholar 

  43. 43.

    Lee HA, Lee DY, Cho HM, Kim SY, Iwasaki Y, Kim IK. Histone deacetylase inhibition attenuates transcriptional activity of mineralocorticoid receptor through its acetylation and prevents development of hypertension. Circ Res. 2013;112:1004–12.

    CAS  PubMed  Google Scholar 

  44. 44.

    Aoi W, Niisato N, Sawabe Y, Miyazaki H, Tokuda S, Nishio K, et al. Abnormal expression of ENaC and SGK1 mRNA induced by dietary sodium in Dahl salt-sensitively hypertensive rats. Cell Biol Int. 2007;31:1288–91.

    CAS  PubMed  Google Scholar 

  45. 45.

    Kakizoe Y, Kitamura K, Ko T, Wakida N, Maekawa A, Miyoshi T, et al. Aberrant ENaC activation in Dahl salt-sensitive rats. J Hypertens. 2009;27:1679–89.

    CAS  PubMed  Google Scholar 

  46. 46.

    Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, et al. Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature. 1994;367:463–7.

    CAS  PubMed  Google Scholar 

  47. 47.

    Amin MS, Reza E, El-Shahat E, Wang HW, Tesson F, Leenen FH. Enhanced expression of epithelial sodium channels in the renal medulla of Dahl S rats. Can J Physiol Pharmacol. 2011;89:159–68.

    CAS  PubMed  Google Scholar 

  48. 48.

    Pavlov TS, Staruschenko A. Involvement of ENaC in the development of salt-sensitive hypertension. Am J Physiol Ren Physiol. 2017;313:F135–40.

    CAS  Google Scholar 

  49. 49.

    Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T. Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension. 2007;49:355–64.

    CAS  PubMed  Google Scholar 

  50. 50.

    Nagase M, Fujita T. Aldosterone and glomerular podocyte injury. Clin Exp Nephrol. 2008;12:233–42.

    CAS  PubMed  Google Scholar 

  51. 51.

    Felizardo RJF, de Almeida DC, Pereira RL, Watanabe IKM, Doimo NTS, Ribeiro WR, et al. Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms. FASEB J. 2019;33:11894–908.

    CAS  PubMed  Google Scholar 

  52. 52.

    Bock F, Shahzad K, Wang H, Stoyanov S, Wolter J, Dong W, et al. Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc. Proc Natl Acad Sci USA. 2013;110:648–53.

    CAS  PubMed  Google Scholar 

  53. 53.

    Vallee SM, Grillo CA, Gonzalez S, Cosen-Binker L, de Kloet ER, McEwen BS, et al. Further studies in deoxycorticosterone acetate treated rats: brain content of mineralocorticoid and glucocorticoid receptors and effect of steroid antagonists on salt intake. Neuroendocrinology. 1995;61:117–24.

    CAS  PubMed  Google Scholar 

  54. 54.

    Sakai RR, Ma LY, Zhang DM, McEwen BS, Fluharty SJ. Intracerebral administration of mineralocorticoid receptor antisense oligonucleotides attenuate adrenal steroid-induced salt appetite in rats. Neuroendocrinology. 1996;64:425–9.

    CAS  PubMed  Google Scholar 

  55. 55.

    Fu Y, Vallon V. Mineralocorticoid-induced sodium appetite and renal salt retention: evidence for common signaling and effector mechanisms. Nephron Physiol. 2014;128:8–16.

    CAS  PubMed  PubMed Central  Google Scholar 

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This work was supported by the National Natural Science Foundation of China Grant No. 81600322 and No. 81770707.

Author information




LW designed the experiments and drafted the manuscript. QZ supervised the animal experiments and revised the manuscript. CW, ZC, and LZ collected the animal samples and analyzed the effects of NaBu by molecular methods and ELISA tests in tissues and cells. YZ, MD, CH, and YL performed animal experiments and recorded blood pressure.

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Correspondence to Lei Wang.

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Wu, C., Chen, Z., Zhang, L. et al. Sodium butyrate ameliorates deoxycorticosterone acetate/salt-induced hypertension and renal damage by inhibiting the MR/SGK1 pathway. Hypertens Res 44, 168–178 (2021).

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  • DOCA
  • hypertension
  • sodium butyrate
  • MR
  • SGK1


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