Effects of Rikkunshito treatment on renal fibrosis/inflammation and body weight reduction in a unilateral ureteral obstruction model in mice.
Animals
Body Weight
/ drug effects
Disease Models, Animal
Drugs, Chinese Herbal
/ pharmacology
Fibrosis
/ drug therapy
Inflammation
/ drug therapy
Kidney
/ drug effects
Male
Mice
Renal Insufficiency, Chronic
/ drug therapy
Signal Transduction
/ drug effects
Sirtuin 1
/ metabolism
Ureteral Obstruction
/ complications
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
05 02 2020
05 02 2020
Historique:
received:
09
04
2019
accepted:
13
01
2020
entrez:
7
2
2020
pubmed:
7
2
2020
medline:
13
11
2020
Statut:
epublish
Résumé
Chronic kidney disease (CKD) progresses to end-stage renal failure via renal tubulointerstitial fibrosis. Malnutrition, inflammation, and arteriosclerosis interact to exacerbate the poor prognosis of CKD, and their effective management is thus essential. The traditional Japanese medicine Rikkunshito (RKT) exerts appetite-stimulating effects via ghrelin, which attenuates inflammation and fibrosis. We evaluated the therapeutic effect of RKT in unilateral ureter obstruction (UUO)-induced renal fibrosis/inflammation and body weight loss in mice. UUO and sham-operated mice were fed a standard diet or diet containing 3.0% RKT. Renal fibrosis was investigated by histopathology and macrophage infiltration was determined by immunohistochemistry. Expression levels of genes associated with fibrosis, inflammation, ghrelin, and mitochondrial function were determined by quantitative reverse transcription-polymerase chain reaction and western blot analyses. RKT treatment partially prevented UUO-induced weight loss but failed to attenuate renal fibrosis and inflammation. Renal expression of sirtuin 1, a ghrelin-downstream signalling molecule, and gene expression of peroxisome proliferator-activated receptor-γ coactivator 1α and Bcl-2/adenovirus E1B interacting protein 3 were unaffected by RKT. These results indicate that RKT inhibits weight loss but does not improve renal fibrosis or inflammation in a rapidly progressive renal fibrosis mouse model. RKT may have a protective effect on weight loss associated with CKD.
Identifiants
pubmed: 32024850
doi: 10.1038/s41598-020-58214-0
pii: 10.1038/s41598-020-58214-0
pmc: PMC7002622
doi:
Substances chimiques
Drugs, Chinese Herbal
0
liu-jun-zi-tang
0
Sirtuin 1
EC 3.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1782Références
Zyga, S., Christopoulou, G. & Malliarou, M. Malnutrition-inflammation-atherosclerosis syndrome in patients with end-stage renal disease. J. Ren Care 1, 12–5 (2011).
doi: 10.1111/j.1755-6686.2011.00201.x
Akdag, I. et al. Clinical value of the malnutrition-inflammation-atherosclerosis syndrome for long-term prediction of cardiovascular mortality in patients with end-stage renal disease: a 5-year prospective study. Nephron Clin. Pract. 108, c99–c105 (2008).
doi: 10.1159/000113526
Nojiri, T. et al. Protective effects of ghrelin on cisplatin-induced nephrotoxicity in mice. Peptides 82, 85–91 (2016).
doi: 10.1016/j.peptides.2016.06.003
Takeda, H. et al. Rikkunshito ameliorates the aging-associated decrease in ghrelin receptor reactivity via phosphodiesterase III inhibition. Endocrinology 151, 244–252 (2010).
doi: 10.1210/en.2009-0633
Takeda, H. et al. Rikkunshito as a ghrelin enhancer. Methods Enzymol. 514, 333–351 (2012).
doi: 10.1016/B978-0-12-381272-8.00021-0
Meier, U. & Gressner, A. M. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin. Chem. 50, 1511–1525 (2004).
doi: 10.1373/clinchem.2004.032482
Peeters, T. L. Ghrelin: a new player in the control of gastrointestinal functions. Gut 54, 1638–1649 (2005).
doi: 10.1136/gut.2004.062604
pubmed: 1774760
pmcid: 1774760
Delporte, C. Structure and physiological actions of ghrelin. Scientifica (Cairo). 2013, Article ID 518909, 25 pages (2013).
Fujimura, K. et al. Ghrelin protects against renal damages induced by angiotensin-II via an antioxidative stress mechanism in mice. PLoS One 9, e94373 (2014).
doi: 10.1371/journal.pone.0094373
pubmed: 3991592
pmcid: 3991592
Sun, G. X. et al. Ghrelin attenuates renal fibrosis and inflammation of obstructive nephropathy. J. Urol. 193, 2107–2115 (2015).
doi: 10.1016/j.juro.2014.11.098
pubmed: 25481038
pmcid: 25481038
Azushima, K. et al. Effects of rikkunshito on renal fibrosis and inflammation in angiotensin II-infused mice. Sci. Rep. 9, 6201 (2019).
doi: 10.1038/s41598-019-42657-1
pubmed: 30996242
pmcid: 30996242
Matsuda, M. et al. Upstream stimulatory factors 1 and 2 mediate the transcription of angiotensin II binding and inhibitory protein. J. Biol. Chem. 288, 19238–19249 (2013).
doi: 10.1074/jbc.M113.451054
pubmed: 23653383
pmcid: 23653383
Matsuda, M. et al. Involvement of Runx3 in the basal transcriptional activation of the mouse angiotensin II type 1 receptor-associated protein gene. Physiol. Genomics 43, 884–894 (2011).
doi: 10.1152/physiolgenomics.00005.2011
pubmed: 21586669
pmcid: 21586669
Kobayashi, R. et al. An angiotensin II type 1 receptor binding molecule has a critical role in hypertension in a chronic kidney disease model. Kidney Int. 91, 1115–1125 (2017).
doi: 10.1016/j.kint.2016.10.035
pubmed: 28081856
pmcid: 28081856
Ohsawa, M. et al. Deletion of the angiotensin II type 1 receptor-associated protein enhances renal sodium reabsorption and exacerbates angiotensin II-mediated hypertension. Kidney Int. 86, 570–581 (2014).
doi: 10.1038/ki.2014.95
pubmed: 4149871
pmcid: 4149871
Azushima, K. et al. Adipocyte-specific enhancement of angiotensin II type 1 receptor-associated protein ameliorates diet-induced visceral obesity and insulin resistance. J. Am. Heart Assoc. 6, e004488 (2017).
doi: 10.1161/JAHA.116.004488
pubmed: 5524000
pmcid: 5524000
Maeda, A. et al. Angiotensin receptor-binding protein ATRAP/Agtrap inhibits metabolic dysfunction with visceral obesity. J. Am. Heart Assoc. 2, e000312 (2013).
doi: 10.1161/JAHA.113.000312
pubmed: 3828814
pmcid: 3828814
Uneda, K. et al. Angiotensin II type 1 receptor-associated protein regulates kidney aging and lifespan independent of angiotensin. J. Am. Heart Assoc. 6, e006120 (2017).
doi: 10.1161/JAHA.117.006120
pubmed: 5586453
pmcid: 5586453
Kong, W. et al. Renal Fibrosis, Immune Cell Infiltration and Changes of TRPC Channel Expression after Unilateral Ureteral Obstruction in Trpc6−/− Mice. Cell Physiol Biochem. 52, 1484–1502 (2019).
Haruhara, K. et al. Angiotensin receptor-binding molecule in leukocytes in association with the systemic and leukocyte inflammatory profile. Atherosclerosis 269, 236–244 (2018).
doi: 10.1016/j.atherosclerosis.2018.01.013
Wakui, H. et al. Enhanced angiotensin receptor-associated protein in renal tubule suppresses angiotensin-dependent hypertension. Hypertension 61, 1203–1210 (2013).
doi: 10.1161/HYPERTENSIONAHA.111.00572
pubmed: 3657390
pmcid: 3657390
Ohki, K. et al. Angiotensin II type 1 receptor-associated protein inhibits angiotensin II-induced insulin resistance with suppression of oxidative stress in skeletal muscle tissue. Sci. Rep. 8, 2846 (2018).
doi: 10.1038/s41598-018-21270-8
pubmed: 5809432
pmcid: 5809432
Zhang, W. et al. Greater Physiological and Behavioral Effects of Interrupted Stress Pattern Compared to Daily Restraint Stress in Rats. PLoS One. 9, e0102247 (2014).
Larder, R. et al. Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation. Proc Natl Acad Sci USA 114, 9421–9426 (2017).
doi: 10.1073/pnas.1707310114
Fappi, A. et al. The effects of omega-3 fatty acid supplementation on dexamethasone-induced muscle atrophy. Biomed Res Int. 2014, 961438 (2014).
doi: 10.1155/2014/961438
pubmed: 4055633
pmcid: 4055633
Chen, V. P. et al. Butyrylcholinesterase gene transfer in obese mice prevents postdieting body weight rebound by suppressing ghrelin signaling. Proc Natl Acad Sci USA 114, 10960–10965 (2017).
doi: 10.1073/pnas.1706517114
Takeda, H. et al. Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology 134, 2004–2013 (2008).
doi: 10.1053/j.gastro.2008.02.078
Matsumura, T. et al. The traditional Japanese medicine Rikkunshito increases the plasma level of ghrelin in humans and mice. J. Gastroenterol. 45, 300–307 (2010).
doi: 10.1007/s00535-009-0166-z
Cui, H., López, M. & Rahmouni, K. The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat. Rev. Endocrinol. 13, 338–351 (2017).
doi: 10.1038/nrendo.2016.222
Terawaki, K. et al. Development of ghrelin resistance in a cancer cachexia rat model using human gastric cancer-derived 85As2 cells and the palliative effects of the Kampo medicine rikkunshito on the model. PLoS One 12, e0173113 (2017).
doi: 10.1371/journal.pone.0173113
pubmed: 5332064
pmcid: 5332064
Fujitsuka, N. et al. Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival. Transl. Psychiatry 1, e23 (2011).
doi: 10.1038/tp.2011.25
pubmed: 22832525
pmcid: 22832525
Fujitsuka, N. et al. Rikkunshito, a ghrelin potentiator, ameliorates anorexia-cachexia syndrome. Front. Pharmacol. 5, 271 (2014).
doi: 10.3389/fphar.2014.00271
pubmed: 25540621
pmcid: 25540621
Kovesdy, C. P. et al. Paradoxical association between body mass index and mortality in men with CKD not yet on dialysis. Am. J. Kidney Dis. 49, 581–91 (2007).
doi: 10.1053/j.ajkd.2007.02.277
pubmed: 17472839
pmcid: 17472839
Pereira, R. A. et al. Sarcopenia in chronic kidney disease on conservative therapy: prevalence and association with mortality. Nephrol. Dial. Transplant. 30, 1718–25 (2015).
doi: 10.1093/ndt/gfv133
pubmed: 25999376
pmcid: 25999376
Fahal, I. H. Uraemic sarcopenia: aetiology and implications. Nephrol. Dial. Transplant. 29, 1655–65 (2014).
doi: 10.1093/ndt/gft070
pubmed: 23625972
pmcid: 23625972
Sato, E. et al. Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease. Sci. Rep. 6, 36618 (2016).
doi: 10.1038/srep36618
pubmed: 27830716
pmcid: 27830716
Fujitsuka, N. et al. Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1. Mol. Psychiatry 21, 1613–1623 (2016).
doi: 10.1038/mp.2015.220
pubmed: 26830139
pmcid: 26830139
Shimada, T. et al. Des-acyl ghrelin protects microvascular endothelial cells from oxidative stress-induced apoptosis through sirtuin 1 signaling pathway. Metabolism 63, 469–474 (2014).
doi: 10.1016/j.metabol.2013.12.011
pubmed: 24486147
pmcid: 24486147
Yang, S. Y. et al. A low-salt diet increases the expression of renal sirtuin 1 through activation of the ghrelin receptor in rats. Sci. Rep. 6, 32787 (2016).
doi: 10.1038/srep32787
pubmed: 27600292
pmcid: 27600292
Tang, B. L. Sirt1 and the mitochondria. Mol. Cells 39, 87–95 (2016).
doi: 10.14348/molcells.2016.2318
pubmed: 4757807
pmcid: 4757807
Stenvinkel, P. & Larsson, T. E. Chronic kidney disease: a clinical model of premature aging. Am. J. Kidney Dis. 62, 339–351 (2013).
doi: 10.1053/j.ajkd.2012.11.051
Yakabi, K. et al. Rikkunshito and 5-HT2C receptor antagonist improve cisplatin-induced anorexia via hypothalamic ghrelin interaction. Regul. Pept. 161, 97–105 (2010).
doi: 10.1016/j.regpep.2010.02.003
Huang, L. et al. Development of a chronic kidney disease model in C57BL/6 mice with relevance to human pathology. Nephron Extra 3, 12–29 (2013).
doi: 10.1159/000346180
pubmed: 3617971
pmcid: 3617971
Jadot, I. et al. An integrated view of aristolochic acid nephropathy: Update of the literature. Int. J. Mol. Sci. 18, E297 (2017).
doi: 10.3390/ijms18020297
Jia, T. et al. A novel model of adenine-induced tubulointerstitial nephropathy in mice. BMC Nephrol. 14, 116 (2013).
doi: 10.1186/1471-2369-14-116
pubmed: 3682934
pmcid: 3682934