Clinical and Experimental Nephrology

, Volume 17, Issue 6, pp 848–856 | Cite as

Serum level of soluble (pro)renin receptor is modulated in chronic kidney disease

  • Kazu Hamada
  • Yoshinori Taniguchi
  • Yoshiko Shimamura
  • Kosuke Inoue
  • Koji Ogata
  • Masayuki Ishihara
  • Taro Horino
  • Shimpei Fujimoto
  • Takashi Ohguro
  • Yukio Yoshimoto
  • Mika Ikebe
  • Kenji Yuasa
  • Eri Hoshino
  • Tatsuo Iiyama
  • Atsuhiro Ichihara
  • Yoshio Terada
Original Article

Abstract

Background

Prorenin, the precursor of renin, binds to the (pro)renin receptor [(P)RR] and triggers intracellular signaling. The ligand binding sites of (P)RR are disconnected and are present in the soluble form of the receptor in serum. Given that the clinical significance of serum prorenin and soluble (P)RR in chronic kidney disease (CKD) is unclear, we investigated the relationship between serum prorenin, soluble (P)RR, and various clinical parameters in patients with CKD.

Methods

A total of 374 patients with CKD were enrolled. Serum samples were collected, and the levels of soluble (P)RR and prorenin were measured using ELISA kits. Serum creatinine (Cr), blood urea nitrogen (BUN), uric acid (UA), hemoglobin (Hb), soluble secreted α-Klotho, and the urine protein/Cr ratio were also measured. Similarly, clinical parameters were also evaluated using serum and urine sample collected after 1 year (n = 204).

Results

Soluble (P)RR levels were positively associated with serum Cr (P < 0.0001, r = 0.263), BUN (P < 0.0001, r = 0.267), UA (P < 0.005, r = 0.168) levels, CKD stage (P < 0.0001, r = 0.311) and urine protein/Cr ratio (P < 0.01, r = 0.157), and inversely with estimated glomerular infiltration rate (eGFR) (P < 0.0001, r = −0.275) and Hb (P < 0.005, r = −0.156). Soluble (P)RR levels were inversely associated with α-Klotho levels (P < 0.001, r = −0.174) but did not correlate with prorenin levels. With respect to antihypertensive drugs, soluble (P)RR levels were significantly lower in patients treated with an angiotensin II receptor blocker (ARB) than in those without ARB therapy (P < 0.005). Soluble (P)RR levels were significantly lower in CKD patients with diabetes mellitus or primary hypertension than in those without these conditions (P < 0.05). In contrast, serum levels of prorenin did not correlate with parameters related to renal function. Serum prorenin levels were significantly higher in CKD patients with diabetes mellitus than in nondiabetic patients (P < 0.05), but not in CKD patients with hypertension (P = 0.09). Finally, with respect to the relationship between basal soluble (P)RR levels and the progression rates of renal function, soluble (P)RR levels were positively associated with ΔCr (P < 0.05, r = 0.159) and inversely associated with ΔeGFR (P < 0.05, r = −0.148).

Conclusion

Serum levels of soluble (P)RR correlated with the stage of CKD. Our findings suggest that soluble (P)RR may be involved in renal injury and influence the progression of CKD.

Keywords

Prorenin Soluble (pro)renin receptor Chronic kidney disease 

References

  1. 1.
    Weir MR, Dzau VJ. The renin–angiotensin–aldosterone system: a specific target for hypertension management. Am J Hypertens. 1999;12:205S–13S.PubMedCrossRefGoogle Scholar
  2. 2.
    Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev. 2000;52:11–34.PubMedGoogle Scholar
  3. 3.
    Dzau VJ, Bernstein K, Celermajer D, Cohen J, Dahlöf B, Deanfield J, Diez J, Drexler H, Ferrari R, van Gilst W, Hansson L, Hornig B, Husain A, Johnston C, Lazar H, Lonn E, Lüscher T, Mancini J, Mimran A, Pepine C, Rabelink T, Remme W, Ruilope L, Ruzicka M, Schunkert H, Swedberg K, Unger T, Vaughan D, Weber M. The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data. Am J Cardiol. 2001;88:1L–20L.PubMedCrossRefGoogle Scholar
  4. 4.
    Derkx FH, Schalekamp MA. Human prorenin: pathophysiology and clinical implications. Clin Exp Hypertens A. 1988;10:1213–25.Google Scholar
  5. 5.
    Luetscher JA, Kraemer FB, Wilson DM, Schwartz HC, Bryer-Ash M. Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications. N Engl J Med. 1985;312:1412–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Wilson DM, Luetscher JA. Plasma prorenin activity and complications in children with insulin-dependent diabetes mellitus. N Engl J Med. 1990;323:1101–6.Google Scholar
  7. 7.
    Nguyen G, Delarue F, Berrou J, Rondeau E, Sraer JD. Specific receptor bindingofreninonhuman mesangial cells in cultureincreasesplasminogen activator-1 antigen. Kidney Int. 1996;50:1897–903.PubMedCrossRefGoogle Scholar
  8. 8.
    Nguyen G, Delarue F, Burcklé C, Bouzhir L, Giller T. SraerJD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest. 2002;109:1417–27.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Huang Y, Wongamorntham S, Kasting J, McQuillan D, Owens RT, Yu L, Noble NA, Border W. Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int. 2006;69:105–13.PubMedCrossRefGoogle Scholar
  10. 10.
    Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.PubMedCrossRefGoogle Scholar
  11. 11.
    Schalekamp MADH, Derkx FH, Deinum J, Danser AJ. Newly developed rennin and prorenin assays and the clinical evaluation of rennin inhibitors. J Hypertens. 2008;26:928–37.PubMedCrossRefGoogle Scholar
  12. 12.
    Watanabe N, Bokuda K, Fujiwara T, Suzuki T, Mito A, Morimoto S, Jwa SC, Egawa M, Arai Y, Suzuki F, Sago H, Ichihara A. Soluble (pro)renin receptor and blood pressure during pregnancy: a prospective cohort study. Hypertension. 2012;60:1250–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Advani A, Kelly DJ, Cox AJ, White KE, Advani SL, Thai K, Connelly KA, Yuen D, Trogadis J, Herzenberg AM, Kuliszewski MA, Leong-Poi H, Gilbert RE. The (Pro)renin receptor: site-specific and functional linkage to the vacuolar H+–ATPase in the kidney. Hypertension. 2009;54:261–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Hirose T, Mori N, Totsune K, Morimoto R, Maejima T, Kawamura T, Metoki H, Asayama K, Kikuya M, Ohkubo T, Kohzuki M, Takahashi K, Imai Y. Increased expression of (pro)renin receptor in the remnant kidneys of 5/6 nephrectomized rats. Regul Pept. 2010;159:93–9.Google Scholar
  15. 15.
    Ichihara A, Itoh H, Inagami T. Critical roles of (pro)renin receptor-boundprorenin in diabetes andhypertension: salliesintotherapeutic approach. J Am Soc Hypertens. 2008;2:15–9.Google Scholar
  16. 16.
    Cruciat CM, Ohkawara B, Acebron SP, Karaulanov E, Reinhard C, Ingelfinger D, Boutros M, Niehrs C. Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science. 2010;327:459–63.PubMedCrossRefGoogle Scholar
  17. 17.
    Gonzalez AA, Lara LS, Luffman C, Seth DM, Prieto MC. Soluble form of the (pro)renin receptor is augmented in the collecting duct and urine of chronic angiotensin II-dependent hypertensive rats. Hypertension. 2011;57:859–64.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Ichihara A. (Pro)renin receptor and autophagy in podocytes. Autophagy. 2012;8:271–2.PubMedCrossRefGoogle Scholar
  19. 19.
    Schefe JH, Menk M, Reinemund J, Effertz K, Hobbs RM, Pandolfi PP, Ruiz P, Unger T, Funke-Kaiser H. A novel signal transduction cascade involving direct physical interaction of the renin/prorenin receptor with the transcription factor promyelocytic zinc finger protein. Circ Res. 2006;99:1355–66.PubMedCrossRefGoogle Scholar
  20. 20.
    Nguyen G, Contrepas A. Physiology and pharmacology of the (pro)renin receptor. Curr Opin Pharmacol. 2008;8:127–32.PubMedCrossRefGoogle Scholar
  21. 21.
    Siragy HM, Huang J. Renal (pro)renin receptor regulation in diabetic ratsthrough enhanced angiotensin AT1 receptor and NADPH oxidase activity. Exp Physiol. 2008;93:709–14.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Kurtz A, Wagner C. Regulation of renin secretin by angiotensin II-AT1 receptor. J Am Soc Nephrol. 1999;19:162–8.Google Scholar
  23. 23.
    Siragy HM, Awad A, Abadir P, Webb R. The angiotensin II type 1 receptor mediates renal interstitial content of tumor necrosis factor-α in diabetic rats. Endocrinology. 2003;144:2229–33.PubMedCrossRefGoogle Scholar
  24. 24.
    Sodhi CP, Kanwar YS, Sahai A. Hypoxia and high glucose upregulate AT1 receptor expression and potentiate ANG II-induced proliferation in VSM cells. Am J Physiol Heart Circ Physiol. 2003;284:846–52.Google Scholar
  25. 25.
    Privratsky JR, Wold LE, Sowers JR, Quinn MT, Ren J. AT1 blockade prevents glucose-induced cardiac dysfunction in ventricular myocytes: role of the AT1 receptor and NADPH oxidase. Hypertension. 2003;42:206–12.PubMedCrossRefGoogle Scholar
  26. 26.
    Onozato ML, Toji A, Goto A, Fujita T, Wilcox CS. Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB. Kidney Int. 2002;61:186–94.PubMedCrossRefGoogle Scholar
  27. 27.
    Ferri N, Greco CM, Corsini GMA. Aliskiren reduces prorenin receptor expression and activity in cultured human aortic smooth muscle cells. J Renin Angiotensin Aldosterone Syst. 2011;12:469–74.PubMedCrossRefGoogle Scholar
  28. 28.
    Feldman DL, Jin L, Xuan H, Contrepas A, Zhou Y, Webb RL, Mueller DN, Feldt S, Cumin F, Maniara W, Persohn E, Schuetz H, Jan Danser AH, Nguyen G. Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension. 2008;52:130–6.Google Scholar
  29. 29.
    Lu H, Rateri DL, Feldman DL, Jr RJ, Fukamizu A, Ishida J, Oesterling EG, Cassis LA, Daugherty A. Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice. J Clin Invest. 2008;118:984–93.Google Scholar
  30. 30.
    Brown MJ. Aliskiren. Circulation. 2008;118:773–84.PubMedCrossRefGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2013

Authors and Affiliations

  • Kazu Hamada
    • 1
  • Yoshinori Taniguchi
    • 1
  • Yoshiko Shimamura
    • 1
  • Kosuke Inoue
    • 1
  • Koji Ogata
    • 1
  • Masayuki Ishihara
    • 1
  • Taro Horino
    • 1
  • Shimpei Fujimoto
    • 1
  • Takashi Ohguro
    • 2
  • Yukio Yoshimoto
    • 2
  • Mika Ikebe
    • 3
  • Kenji Yuasa
    • 3
  • Eri Hoshino
    • 4
  • Tatsuo Iiyama
    • 4
  • Atsuhiro Ichihara
    • 5
  • Yoshio Terada
    • 1
  1. 1.Department of Endocrinology, Metabolism and NephrologyKochi University School of MedicineNankokuJapan
  2. 2.Department of Internal MedicineKochi Red Cross HospitalKochiJapan
  3. 3.Department of Urology and Internal MedicineKochi-Takasu HospitalKochiJapan
  4. 4.Clinical Trial CenterKochi University School of MedicineKochiJapan
  5. 5.Department of Endocrinology and HypertensionTokyo Women’s Medical UniversityTokyoJapan

Personalised recommendations