A Novel Aldosterone Antagonist Limits Renal Injury in 5/6 Nephrectomy

Scientific Reports

Volumn 7, Issue 1, 2017, Pages

  Fujihara, Clarice K ^a   Kowala, M C ^b   Breyer, M D ^b   Sena, Claudia R ^a   Rodrigues, Mariliza V ^a   Arias, Simone C A ^a   Fanelli, Camilla ^a   Malheiros, Denise M ^a   Jadhav, P K ^b   Montrose Rafizadeh, Chahrzad ^b   Krieger, Jose E ^a   Zatz, Roberto ^a  

^a UNIVERSITY OF SÃO PAULO   (Brazil)

^b ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALDOSTERONE; EPLERENONE; LOSARTAN; MINERALOCORTICOID ANTAGONIST; RENIN;

ALBUMINURIA; ANIMAL; BLOOD; BLOOD PRESSURE; CHRONIC KIDNEY FAILURE; NEPHRECTOMY; TREATMENT OUTCOME; WISTAR RAT;

ALBUMINURIA; ALDOSTERONE; ANIMALS; BLOOD PRESSURE; EPLERENONE; LOSARTAN; MINERALOCORTICOID RECEPTOR ANTAGONISTS; NEPHRECTOMY; RATS, WISTAR; RENAL INSUFFICIENCY, CHRONIC; RENIN; TREATMENT OUTCOME;

EID: 85048965970     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/s41598-017-08383-2     Document Type: Article

References (36)

1. Brown, N. J. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat. Rev. Nephrol. 9, 459–469 (2013).
2. Bianchi, S., Batini, V. & Bigazzi, R. The renal effects of mineralocorticoid receptor antagonists. Int. J. Cardiol. 200, 20–24 (2015).
3. Aldigier, J. C., Kanjanbuch, T., Ma, L. J., Brown, N. J. & Fogo, A. B. Regression of existing glomerulosclerosis by inhibition of aldosterone. J. Am. Soc. Nephrol. 16, 3306–3314 (2005).
4. Chen, H. et al. Eplerenone-mediated aldosterone blockade prevents renal fibrosis by reducing renal inflammation, interstitial cell proliferation and oxidative stress. Kidney Blood Press Res. 37, 557–566 (2013).
5. Ikeda, H. et al. Spironolactone suppresses inflammation and prevents L-NAME-induced renal injury in rats. Kidney Int 75, 147–155 (2009).
6. Nagase, M. et al. Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors. J. Am. Soc. Nephrol. 17, 3438–3446 (2006).
7. Kolkhof, P., Nowack, C. & Eitner, F. Nonsteroidal antagonists of the mineralocorticoid receptor. Curr. Opin. Nephrol. Hypertens. 24, 417–424 (2015).
8. Haller, H., Bertram, A., Stahl, K. & Menne, J. Finerenone: a New Mineralocorticoid Receptor Antagonist Without Hyperkalemia: an Opportunity in Patients with CKD? Curr. Hypertens. Rep. 18, 41 (2016).
9. Meyers, M. J. et al. Discovery of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g] indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy. J. Med. Chem. 53, 5979–6002 (2010).
10. Bakris, G. L. et al. Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial. J. Am. Med. Assoc. 314, 884–894 (2015).
11. Pitt, B. et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur. Heart J. 34, 2453–2463 (2013).
12. Arias, S. C. et al. Regression of albuminuria and hypertension and arrest of severe renal injury by a losartan-hydrochlorothiazide association in a model of very advanced nephropathy. PLoS One 8, e56215 (2013).
13. Fujihara, C. K., Malheiros, D. M. & Zatz, R. Losartan-hydrochlorothiazide association promotes lasting blood pressure normalization and completely arrests long-term renal injury in the 5/6 ablation model. Am J Physiol. Renal Physiol. 292, F1810–1818 (2007).
14. Fujihara, C. K. et al. Combined mycophenolate mofetil and losartan therapy arrests established injury in the remnant kidney. JASN. 11, 283–290 (2000).
15. Brenner, B. M. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 345, 861–869 (2001).
16. Lewis, E. J. et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 345, 851–860 (2001).
17. Fujisaki, K. et al. Impact of combined losartan/hydrochlorothiazide on proteinuria in patients with chronic kidney disease and hypertension. Hypertens Res. 37, 993–998 (2014).
18. Piecha, G. et al. Regression of glomerulosclerosis in subtotally nephrectomized rats: effects of monotherapy with losartan, spironolactone, and their combination. Am J Physiol. Renal Physiol. 295, F137–144 (2008).
19. Nemeth, Z. et al. Increased renoprotection with ACE inhibitor plus aldosterone antagonist as compared to monotherapies–the effect on podocytes. Nephrol Dial Transplant. 24, 3640–3651 (2009).
20. Schjoedt, K. J. et al. Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int 68, 2829–2836 (2005).
21. Nielsen, S. E. et al. Spironolactone diminishes urinary albumin excretion in patients with type 1 diabetes and microalbuminuria: a randomized placebo-controlled crossover study. Diabet Med. 29, e184–190 (2012).
22. Kim, H. Y., Bae, E. H., Ma, S. K. & Kim, S. W. Effects of spironolactone in combination with angiotensin-converting enzyme inhibitors or Angiotensin receptor blockers in patients with proteinuria. Kidney Blood Press. Res. 39, 573–580 (2014).
23. Tait, J. F. & Tait, S. A. Role of cAMP in the effects of K+ on the steroidogenesis of zona glomerulosa cells. Clin Exp Pharmacol Physiol. 26, 947–955 (1999).
24. Spat, A. Glomerulosa cell–a unique sensor of extracellular K+ concentration. Mol. Cell. Endocrinol. 217, 23–26 (2004).
25. Rodriguez-Iturbe, B. et al. Reduction of renal immune cell infiltration results in blood pressure control in genetically hypertensive rats. Am J Physiol. Renal Physiol. 282, F191–201 (2002).
26. Schrier, R. W. Aldosterone ‘escape’ vs ‘breakthrough’. Nat Rev Nephrol. 6, 61 (2010).
27. Guyton, A. C. Blood pressure control–special role of the kidneys and body fluids. Science 252, 1813–1816 (1991).
28. Nagai, Y. et al. Aldosterone stimulates collagen gene expression and synthesis via activation of ERK1/2 in rat renal fibroblasts. Hypertension 46, 1039–1045 (2005).
29. Arias, S. C. et al. An association of losartan-hydrochlorothiazide, but not losartan-furosemide, completely arrests progressive injury in the remnant kidney. Am J Physiol. Renal Physiol. 310, F135–143 (2016).
30. Alnemri, E. S., Maksymowych, A. B., Robertson, N. M. & Litwack, G. Overexpression and characterization of the human mineralocorticoid receptor. J. Biol. Chem. 266, 18072–18081 (1991).
31. Binart, N., Lombes, M., Rafestin-Oblin, M. E. & Baulieu, E. E. Characterization of human mineralocorticosteroid receptor expressed in the baculovirus system. Proc Natl Acad Sci USA. 88, 10681–10685 (1991).
32. Cheng, Y. & Prusoff, W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 22, 3099–3108 (1973).
33. Joyeux, A. et al. Engineered cell lines as a tool for monitoring biological activity of hormone analogs. Anal Biochem. 249, 119–130 (1997).
34. Jepsen, F. L. & Mortensen, P. B. Interstitial fibrosis of the renal cortex in minimal change lesion and its correlation with renal function. A quantitative study. Virchows Arch A Pathol Anat Histol. 383, 265–270 (1979).
35. Wallenstein, S., Zucker, C. L. & Fleiss, J. L. Some statistical methods useful in circulation research. Circ. Res. 47, 1–9 (1980).
36. Beasley, T. M. & Schumacker, R. E. Multiple regression approach to analyzing contingency tables: Post hoc and planned comparison procedures. The Journal of Experimental Education. 64, 79–93 (1995).