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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
O’Donnell M, Mente A, Yusuf S. Sodium intake and cardiovascular health. Circ Res. 2015;116:1046–57.
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.
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.
Basting T, Lazartigues E. DOCA-salt hypertension: an update. Curr Hypertens Rep. 2017;19:32.
Gomez-Sanchez EP. DOCA/Salt: much more than a model of hypertension. J Cardiovasc Pharmacol. 2019;74:369–71.
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.
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.
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.
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.
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.
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.
Funder JW. Aldosterone, hypertension and heart failure: insights from clinical trials. Hypertens Res. 2010;33:872–5.
Nishiyama A. Pathophysiological mechanisms of mineralocorticoid receptor-dependent cardiovascular and chronic kidney disease. Hypertens Res. 2019;42:293–300.
Nguyen Dinh Cat A, Jaisser F. Extrarenal effects of aldosterone. Curr Opin Nephrol Hypertens. 2012;21:147–56.
Terker AS, Ellison DH. Renal mineralocorticoid receptor and electrolyte homeostasis. Am J Physiol Regul Integr Comp Physiol. 2015;309:R1068–70.
Valinsky WC, Touyz RM, Shrier A. Aldosterone, SGK1, and ion channels in the kidney. Clin Sci (Lond). 2018;132:173–83.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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. https://doi.org/10.1002/mnfr.201800033.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Pavlov TS, Staruschenko A. Involvement of ENaC in the development of salt-sensitive hypertension. Am J Physiol Ren Physiol. 2017;313:F135–40.
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.
Nagase M, Fujita T. Aldosterone and glomerular podocyte injury. Clin Exp Nephrol. 2008;12:233–42.
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.
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.
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.
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.
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.
This work was supported by the National Natural Science Foundation of China Grant No. 81600322 and No. 81770707.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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). https://doi.org/10.1038/s41440-020-00548-3
- sodium butyrate