Serum level of soluble (pro)renin receptor is modulated in chronic kidney disease
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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.
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).
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).
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.
- Weir, MR, Dzau, VJ (1999) The renin–angiotensin–aldosterone system: a specific target for hypertension management. Am J Hypertens 12: pp. 205S-213S CrossRef
- Kim, S, Iwao, H (2000) Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 52: pp. 11-34
- Dzau, VJ, Bernstein, K, Celermajer, D, Cohen, J, Dahlöf, B, Deanfield, J, Diez, J, Drexler, H, Ferrari, R, 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 (2001) The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data. Am J Cardiol 88: pp. 1L-20L CrossRef
- Derkx FH, Schalekamp MA. Human prorenin: pathophysiology and clinical implications. Clin Exp Hypertens A. 1988;10:1213–25.
- Luetscher, JA, Kraemer, FB, Wilson, DM, Schwartz, HC, Bryer-Ash, M (1985) Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications. N Engl J Med 312: pp. 1412-1417 CrossRef
- Wilson DM, Luetscher JA. Plasma prorenin activity and complications in children with insulin-dependent diabetes mellitus. N Engl J Med. 1990;323:1101–6.
- Nguyen, G, Delarue, F, Berrou, J, Rondeau, E, Sraer, JD (1996) Specific receptor bindingofreninonhuman mesangial cells in cultureincreasesplasminogen activator-1 antigen. Kidney Int 50: pp. 1897-1903 CrossRef
- Nguyen, G, Delarue, F, Burcklé, C, Bouzhir, L, Giller, T (2002) SraerJD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 109: pp. 1417-1427
- Huang, Y, Wongamorntham, S, Kasting, J, McQuillan, D, Owens, RT, Yu, L, Noble, NA, Border, W (2006) Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int 69: pp. 105-113 CrossRef
- Matsuo, S, Imai, E, Horio, M, Yasuda, Y, Tomita, K, Nitta, K, Yamagata, K, Tomino, Y, Yokoyama, H, Hishida, A (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53: pp. 982-992 CrossRef
- Schalekamp, MADH, Derkx, FH, Deinum, J, Danser, AJ (2008) Newly developed rennin and prorenin assays and the clinical evaluation of rennin inhibitors. J Hypertens 26: pp. 928-937 CrossRef
- Watanabe, N, Bokuda, K, Fujiwara, T, Suzuki, T, Mito, A, Morimoto, S, Jwa, SC, Egawa, M, Arai, Y, Suzuki, F, Sago, H, Ichihara, A (2012) Soluble (pro)renin receptor and blood pressure during pregnancy: a prospective cohort study. Hypertension 60: pp. 1250-1256 CrossRef
- 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 (2009) The (Pro)renin receptor: site-specific and functional linkage to the vacuolar H+–ATPase in the kidney. Hypertension 54: pp. 261-269 CrossRef
- 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.
- 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.
- Cruciat, CM, Ohkawara, B, Acebron, SP, Karaulanov, E, Reinhard, C, Ingelfinger, D, Boutros, M, Niehrs, C (2010) Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science 327: pp. 459-463 CrossRef
- Gonzalez, AA, Lara, LS, Luffman, C, Seth, DM, Prieto, MC (2011) Soluble form of the (pro)renin receptor is augmented in the collecting duct and urine of chronic angiotensin II-dependent hypertensive rats. Hypertension 57: pp. 859-864 CrossRef
- Ichihara, A (2012) (Pro)renin receptor and autophagy in podocytes. Autophagy 8: pp. 271-272 CrossRef
- Schefe, JH, Menk, M, Reinemund, J, Effertz, K, Hobbs, RM, Pandolfi, PP, Ruiz, P, Unger, T, Funke-Kaiser, H (2006) A novel signal transduction cascade involving direct physical interaction of the renin/prorenin receptor with the transcription factor promyelocytic zinc finger protein. Circ Res 99: pp. 1355-1366 CrossRef
- Nguyen, G, Contrepas, A (2008) Physiology and pharmacology of the (pro)renin receptor. Curr Opin Pharmacol 8: pp. 127-132 CrossRef
- Siragy, HM, Huang, J (2008) Renal (pro)renin receptor regulation in diabetic ratsthrough enhanced angiotensin AT1 receptor and NADPH oxidase activity. Exp Physiol 93: pp. 709-714 CrossRef
- Kurtz, A, Wagner, C (1999) Regulation of renin secretin by angiotensin II-AT1 receptor. J Am Soc Nephrol 19: pp. 162-168
- Siragy, HM, Awad, A, Abadir, P, Webb, R (2003) The angiotensin II type 1 receptor mediates renal interstitial content of tumor necrosis factor-α in diabetic rats. Endocrinology 144: pp. 2229-2233 CrossRef
- Sodhi, CP, Kanwar, YS, Sahai, A (2003) Hypoxia and high glucose upregulate AT1 receptor expression and potentiate ANG II-induced proliferation in VSM cells. Am J Physiol Heart Circ Physiol 284: pp. 846-852
- Privratsky, JR, Wold, LE, Sowers, JR, Quinn, MT, Ren, J (2003) AT1 blockade prevents glucose-induced cardiac dysfunction in ventricular myocytes: role of the AT1 receptor and NADPH oxidase. Hypertension 42: pp. 206-212 CrossRef
- Onozato, ML, Toji, A, Goto, A, Fujita, T, Wilcox, CS (2002) Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB. Kidney Int 61: pp. 186-194 CrossRef
- Ferri, N, Greco, CM, Corsini, GMA (2011) Aliskiren reduces prorenin receptor expression and activity in cultured human aortic smooth muscle cells. J Renin Angiotensin Aldosterone Syst 12: pp. 469-474 CrossRef
- 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.
- 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.
- Brown, MJ (2008) Aliskiren. Circulation 118: pp. 773-784 CrossRef
- Serum level of soluble (pro)renin receptor is modulated in chronic kidney disease
Clinical and Experimental Nephrology
Volume 17, Issue 6 , pp 848-856
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- Springer Japan
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- Soluble (pro)renin receptor
- Chronic kidney disease
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- Author Affiliations
- 1. Department of Endocrinology, Metabolism and Nephrology, Kochi University School of Medicine, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
- 2. Department of Internal Medicine, Kochi Red Cross Hospital, Kochi, Japan
- 3. Department of Urology and Internal Medicine, Kochi-Takasu Hospital, Kochi, Japan
- 4. Clinical Trial Center, Kochi University School of Medicine, Kochi, Japan
- 5. Department of Endocrinology and Hypertension, Tokyo Women’s Medical University, Tokyo, Japan