(Pro)Renin Receptor Ameliorates the Kidney Damage in the Non-Clipped Kidney of Goldblatt Hypertension

COMMENTARY

Chronic blockade of the (pro)renin receptor ameliorates the kidney damage in the non-clipped kidney of Goldblatt hypertension

Hideyasu Kiyomoto and Kumiko Moriwaki

Hypertension Research (2011) 34, 289–291; doi:10.1038/hr.2010.253; published online 23 December 2010

enin was discovered by Robert Tigerstedt tor blockers have been utilized for not only through extracellular signal-regulated kinase R in 1898; since then, the serial enzymes hypertension, but also diabetes nephropathy, (ERK)1/2 stimulation, (pro)renin receptors and peptides involved in the renin-angioten- metabolic syndrome and heart failure in the upregulate inflammatory mediators, such as sin system (RAS) have been discovered and last decade.2 The initial enzymatic action of cyclooxygenase-2, interleukin-1b and tumor investigated in numerous studies. Accumu- the RAS is the conversion of angiotensinogen necrosis factor-a.5–7 Non-proteolytic activa- lated evidence indicates that the RAS has a (ATG) to angiotensin I (AngI) by renin. The tion of prorenin involves a conformational crucial role in regulating the homeostasis of plasma concentration of AngI is only change that results in the unfolding of the circulation and in maintaining blood pressure approximately twice that of AngII, even prosegment without any cleavage. Although through vasoconstriction of the vasculature when the RAS is activated. Surprisingly, the this reversible open conformation has only and the reabsorption of salt and water in the concentration of ATG is approximately 5000- been achieved in vitro under low pH or kidneys. Humans can very easily obtain abun- fold higher than that of AngI.3 This phenom- cold temperature conditions, it suggested dant salt in modern life, and as a consequence enon indicates that a conversion of ATG to that non-proteolytic activation is possible, we have developed hypertension, which is AngI seems to be the bottleneck in the but not yet defined in vivo.8,9 associated with local activation of the RAS. process; in other words, this reaction is the As a 43-amino acid prosegment covers the As a result, the RAS in humans has been rate-limiting step of the RAS cascade. There- active site cleft and protects the site of the recently been shown an aspect of the ‘evil’ to fore, utilizing the concept of renin inhibition enzymatic activity that converts ATG to AngI, accelerate some disease processes, such as is a logical approach to the management of prorenin is usually inactive even at high heart disease and renal failure. In other hypertension; the first direct renin inhibitor, concentrations in the plasma. Under physio- words, this beautiful and excellent system aliskiren, has recently been marketed as a logical conditions, the plasma prorenin/renin may have become a nuisance in modern treatment for hypertension.3 ratio is B10/1 (see ref. 10). Although high life. Therefore, many inhibitors of the RAS Although more than 100 years have passed, prorenin levels are found in the maternal have been developed to treat human hyper- since the discovery of renin, prorenin had plasma during pregnancy, prorenin obviously tension as well as cardiovascular and renal long been believed to be an inactive precursor does not cause any tissue damage.11 Human disease. of renin in the RAS. Recently, the (pro)renin diabetic patients also display three- to seven- The first description of RAS blockade as a receptor, which binds to both renin and fold higher prorenin/renin ratios in the therapeutic approach occurred in 1957 by prorenin, was identified. Prorenin binding blood,12 which may be associated with the Skeggs et al.1 Among the components of the to (pro)renin receptors results in the cleavage disease progression of interstitial accumula- RAS, angiotensin II (AngII), which is one of of ATG into AngI and triggers the activation tion of AngII in the kidney. Therefore, Suzuki most potent vasoconstrictors in the cardio- of (pro)renin receptor-stimulated signal et al.9 utilized the handle region peptide vascular system, is generated in a step-wise transduction pathways, which are indepen- (HRP) of the prorenin molecule for studies enzymatic cascade. To prevent the pathophy- dent of the production of AngII. In the last on diabetic animals. siological actions of AngII, angiotensin recep- decade, it has been reported that the intra- The peptide inhibitor, HRP, was designed cellular signaling pathway is activated by as a decoy for prorenin on the basis of the

Dr H Kiyomoto is at the Division of Nephrology, Endo- prorenin in cardiomyocytes, mesangial cells, prorenin ‘handle region’ sequence described 9 crinology and Vascular Medicine, Department of Medi- podocytes, distal tubular cells, vascular by Suzuki et al., which interacts with the cine, Tohoku University Graduate School of Medicine, endothelial cells and vascular smooth muscle (pro)renin receptor that was cloned by Sendai, Japan and Dr K Moriwaki is at the Division of cells, which indicates that prorenin mediates Nguyen et al.in2002(seeref.13).Inaseries Nephrology and Hypertension, University of Miami, Leonard M. Miller School of Medicine, Miami, FL, USA intracellular effects in various cardiovascular of seminal experiments, the beneﬁcial effects E-mail: [email protected] and kidney cells.4 In the kidney tissue, of HRP were revealed in the kidney damage Commentary 290

models of experimental diabetes. For exam- effect of HRP on the slowly progressive ing the pathophysiological roles of the RAS in ple, long-term treatment with HRP in strep- nephropathy that occurred in the non- various diseases. Taken together, the combi- tozotocin-induced diabetic rats prevented the clipped kidney of the two-kidneys, one-clip nation therapy of RAS blockade in addition development of proteinuria and glomerulo- renovascular hypertension model. Although to the inhibition of prorenin action might sclerosis, despite hyperglycemia.14 Acontin- HRP treatment did not reduce the blood prevent unprecedented organ damage in var- uous administration of HRP was also able to pressure in Goldblatt rats, the long term ious types of cardiovascular and renal diseases reverse the established diabetic nephropa- administration of HRP for 12 weeks sig- in the near future. thy.15 Moreover, Ichihara et al.16 also revealed nificantly ameliorated the glomerulosclerosis Finally, the (pro)renin receptor has been the efficacy of HRP in angiotensin converting and tubulointerstitial damage with reduc- recently shown to be identical to the vacuolar enzyme (ACE) inhibitor-treated diabetic mice tion in the AngII levels and transforming H+-ATPase, which was formerly discovered in that were deficient in the AT1a receptor. Despite growth factor (TGF)-b mRNA levels in adrenal chromaffin cells,28 and subsequently the insensitivity to AngII in these mice, they the non-clipped kidneys. Yet, in the clipped the (pro)renin receptor’s name was changed still developed glomerulosclerosis, which was kidney, activated prorenin levels, AngII levels, to (P)RR/ATP6ap2.(see ref. 29) Recent data, consistent with observations that RAS block- and TGF-b mRNA levels were similar mainly from fish and frog models, revealed ers are unable to completely prevent the between the HRP- and scramble-peptide- that (P)RR/ATP6ap2 contributes to essential kidney damage associated with diabetes.17,18 treated animals. As the ischemic changes functions in cellular physiology and signaling Thus, it is noteworthy that HRP could effi- that occurred in the clipped kidneys may be that are independent of the RAS.30,31 It is ciently block the progression of glomerulo- mainly affected by hypoxia-inducible fac- unknown whether an excessive inhibition of sclerosis in the AT1a receptor knock-out tors,23 HRP may not evoke the beneficial (P)RR/ATP6ap2 in combination with aliski- mice, meaning that the (pro)renin receptor effects on the clipped kidneys. In contrast, ren, angiotensin receptor blockers and/or has a critical role in diabetic nephropathy.16 the long-term treatment with HRP prevents angiotensin-converting enzyme inhibitors After the epoch-making reports by Ichi- the glomerular and tubular damage that might cause unknown adverse effects because hara et al.,14 we wondered whether HRP develop chronically in the non-clipped kid- the conditional (P)RR/ATP6ap2 knock-out could prevent any kind of kidney disease. neys in the 2K1C models. In other words, the mice could not survive more than 3 weeks, Regrettably, the nephropathy that occurred only difference between the previous report20 which suggests that vacuolar H+-ATPase- acutely in the clipped kidney of Goldblatt and the study done by Ryuzaki et al.22 is associated protein is essential for cell survival hypertensive rats that were treated with HRP simply in the longer duration of administra- independent of the RAS.32 Thus, at least, for 2 weeks did not improve.19 Feldt et al.20 tion of HRP in the Goldblatt hypertensive pregnant women, neonates and infants also could not reduce mortality and nephro- model, which suggests that the effect of HRP should basically avoid these inhibitors. Future sclerosis with HRP in hypertension models, was dependent on the treatment length, but prospective studies and additional evidence such as double-transgenic rats overexpressing not on the dosage of HRP. In contrast to are needed to assess whether inhibition of human renin and ATG, whereas a direct renin aliskiren, because HRP did not reduce the renin and/or prorenin are effective and safe in inhibitor such as aliskiren may improve kid- blood pressure, the effect of HRP is only cardiovascular and kidney disease. ney damage. It can be argued that such expected in chronic administration and hypertensive models not only display high therefore was not observed in the acute CONFLICT OF INTEREST prorenin levels, but also high plasma renin phase of the Goldblatt hypertensive model. The authors declare no conflict of interest. and AngII levels. As HRP blocks only pro- Aliskiren, a direct oral renin inhibitor, renin and not renin binding to (pro)renin competitively inhibited the renin activities Acknowledgements receptors, HRP apparently exerts its effect of receptor-bound forms of both renin and This article was supported in part by a Grant- 24 25 only in diseases that are associated with prorenin in vitro. Nussberger et al. in-Aid for Progressive Renal Diseases Research, high prorenin and low renin levels. Susic reported that both aliskiren and irbesartan from the Ministry of Health, Labour and Welfare et al.21 were also able to confirm only a significantly prevented atherosclerosis pro- of Japan. The author (HK) is also supported mild beneficial effect of HRP on cardiac gression in ApoE knockout mice in the by grants-in-aid for scientific research from the hypertrophy in spontaneously hypertensive 2K1C renovascular hypertension model. In Ministry of Education, Culture, Sports, Science, rats. Therefore, it seems unreliable that HRP human cultured podocytes, aliskiren is the and Technology of Japan (#21591055). function is promoted only in conditions of most potent inhibitor of intracellular AngII upregulated prorenin. levels among RAS inhibitors and does not As described above, it is unfortunate that affect (pro)renin receptor signals, such as 1 Skeggs LT, Kahn JR, Lentz K, Shumway NP. The 26 preparation, purification, and amino acid sequence of HRP did not evoke the protective effect on ERK phosphorylation. Moreover, a recent a polypeptide renin substrate. JExpMed1957; 106: hypertensive nephrosclerosis in Goldblatt rats clinical study indicates that an administration 439–453. even at concentrations as high as 10 mmol/l.19 of aliskiren in addition to losartan reduced 2 Sofue T, Kiyomoto H. Angiotensin II receptor blocker is a renoprotective remedy for metabolic syndrome. There is much confusion concerning the albuminuria and renal dysfunction in Hypertens Res 2009; 32: 735–737. mode of action of HRP, and the basis of the patients with type 2 diabetes, hypertension 3 Hollenberg NK. Direct renin inhibition and the kidney. discrepancy between the in vitro and in vivo and nephropathy.27 In clinical medicine, dia- Nat Rev Nephrol 2010; 6:49–55. 4 Hitom H, Liu G, Nishiyama A. Role of (pro)renin data is unknown. Overall, the HRP results in betic patients sometimes show orthostatic receptor in cardiovascular cells from the aspect of the animal models were disappointing, hypotension caused by inappropriate RAS signaling. Front Biosci 2010; 2: 1246–1249. 22 5 Kaneshiro Y, Ichihara A, Takemitsu T, Sakoda M, Suzuki although Ryuzaki et al. clearly showed inhibition; therefore, inhibition of prorenin F, Nakagawa T, Hayashi M, Inagami T. Increased beneficial effects of HRP in the two-kidneys, would be a good approach for the treatment expression of cyclooxygenase-2 in the renal cortex of one-clip (2KIC) model of hypertensive nephro- of diabetic nephropathy in the absence of human prorenin receptor gene-transgenic rats. Kidney Int 2006; 70: 641–646. sclerosis in an issue of Hypertension Research. hypertension. Based on this, HRP is still an 6 Huang J, Siragy HM. Glucose promotes the produc- They carefully investigated the long-term interesting pharmacological tool for explor- tion of interleukine-1beta and cyclooxygenase-2 in

Hypertension Research Commentary 291

mesangial cells via enhanced (Pro)renin receptor sion of nephropathy developed in diabetes by (Pro)renin binds to renin and prorenin bound to (pro)renin recep- expression. Endocrinology 2009; 150: 5557–5565. receptor blockade. J Am Soc Nephrol 2007; 18: tor in vitro. Hypertens Res 2010; 33: 1053–1059. 7 Matavelli LC, Huang J, Siragy HM. (Pro)renin receptor 2054–2061. 25 Nussberger J, Aubert JF, Bouzourene K, Pellegrin M, contributes to diabetic nephropathy through enhancing 16 Ichihara A, Suzuki F, Nakagawa T, Kaneshiro Y, Take- Hayoz D, Mazzolai L. Renin inhibition by aliskiren renal inflammation. Clin Exp Pharmacol Physiol 2009; mitsu T, Sakoda M, Nabi AH, Nishiyama A, prevents atherosclerosis progression: comparison with 37: 277–282. Sugaya T, Hayashi M, Inagami T. Prorenin receptor irbesartan, atenolol, and amlodipine. Hypertension 8 Pitarresi TM, Rubattu S, Heinrikson R, Sealey JE. blockade inhibits development of glomerulosclerosis 2008; 51: 1306–1311. Reversible cryoactivation of recombinant human pro- in diabetic angiotensin II type 1a receptor-deficient 26 Sakoda M, Ichihara A, Kurauchi-Mito A, Narita T, renin. JBiolChem1992; 267: 11753–11759. mice. JAmSocNephrol2006; 17: 1950–1961. Kinouchi K, Murohashi-Bokuda K, Saleem MA, 9 Suzuki F, Hayakawa M, Nakagawa T, Nasir UM, Ebihara 17 Onozato ML, Tojo A, Goto A, Fujita T, Wilcox CS. Nishiyama A, Suzuki F, Itoh H. Aliskiren inhibits intra- A, Iwasawa A, Ishida Y, Nakamura Y, Murakami K. Oxidative stress and nitric oxide synthase in rat diabetic cellular angiotensin II levels without affecting (pro)re- Human prorenin has ‘gate and handle’ regions for its nephropathy: effects of ACEI and ARB. Kidney Int nin receptor signals in human podocytes. Am J non-proteolytic activation. JBiolChem2003; 278: 2002; 61:186–194. Hypertens 2010; 23:575–580. 22217–22222. 18 Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg 27 Persson F, Lewis JB, Lewis EJ, Rossing P, Hollenberg 10 Danser AH, Derkx FH, Schalekamp MA, Hense HW, NK. Aliskiren combined with losartan in type 2 dia- NK, Parving HH. Impact of baseline renal function on Riegger GA, Schunkert H. Determinants of interindivi- betes and nephropathy. NEnglJMed2008; 358: the efficacy and safety of aliskiren added to losartan in dual variation of renin and prorenin concentrations: 2433–2446. patients withtype 2 diabetes and nephropathy. Diabetes evidence for a sexual dimorphism of (pro)renin levels 19 Muller DN, Klanke B, Feldt S, Cordasic N, Hartner A, Care 2010; 33: 2304–2309. in humans. J Hypertens 1998; 16: 853–862. Schmieder RE, Luft FC, Hilgers KF. (Pro)renin receptor 28 Ludwig J, Kerscher S, Brandt U, Pfeiffer K, 11 Sealey JE, Wilson M, Morganti AA, Zervoudakis I, peptide inhibitor ‘handle-region’ peptide does not Getlawi F, Apps DK, Scha¨gger H. Identification Laragh JH. Changes in active and inactive renin affect hypertensive nephrosclerosis in Goldblatt rats. and characterization of a novel 9.2-kDa membrane throughout normal pregnancy. Clin Exp Hypertens A Hypertension 2008; 51: 676–681. sector-associated protein of vacuolar proton-ATPase 1982; 4: 2373–2384. 20 Feldt S, Maschke U, Dechend R, Luft FC, Muller DN. from chromaffin granules. JBiolChem1998; 273: 12 Deinum J, Ronn B, Mathiesen E, Derkx FH, Hop WC, The putative (pro)renin receptor blocker HRP fails to 10939–10947. Schalekamp MA. Increase in serum prorenin precedes prevent (pro)renin signaling. J Am Soc Nephrol 2008; 29 Sihn G, Rousselle A, Vilianovitch L, Burckle C, Bader onset of microalbuminuria in patients with insulin- 19:743–748. M. Physiology of the (pro)renin receptor: Wnt of dependent diabetes mellitus. Diabetologia 1999; 42: 21 Susic D, Zhou X, Frohlich ED, Lippton H, Knight M. change? Kidney Int 2010; 78:246–256. 1006–1010. Cardiovascular effects of prorenin blockade in geneti- 30 Cruciat CM, Ohkawara B, Acebron SP, Karaulanov E, 13 Nguyen G, Delarue F, Burckle C, Bouzhir L, cally spontaneously hypertensive rats on normal and Reinhard C, Ingelfinger D, Boutros M, Niehrs C. Giller T, Sraer J-D. Pivotal role of the renin/prorenin high-salt diet. Am J Physiol Heart Circ Physiol 2008; Requirement of prorenin receptor and vacuolar receptor in angiotensin II production and 295: H1117–H1121. H+-ATPase-mediated acidification for Wnt signaling. cellular responses to renin. JClinInvest2002; 109: 22 Ryuzaki M, Ichihara A, Oshima Y, Sakoda M, Kurauchi- Science 2010; 327:459–463. 1417–1427. Mito A, Narita T, Kinouchi K, Murohashi-Bokuda K, 31 Amsterdam A, Nissen RM, Sun Z, Swindell EC, Far- 14 Ichihara A, Hayashi M, Kaneshiro Y, Suzuki F, Nishiyama A, Itoh H. Involvement of activated rington S, Hopkins N. Identification of 315 genes Nakagawa T, Tada Y, Koura Y, Nishiyama A, Okada H, prorenin in the pathogenesis of slowly progressive essential for early zebrafish development. Proc Natl Uddin MN, Nabi AH, Ishida Y, Inagami T, Saruta T. nephropathy in the non-clipped kidney of two kidneys, Acad Sci USA 2004; 101: 12792–12797. Inhibition of diabetic nephropathy by a decoy peptide one-clip hypertension. Hypertens Res 2011; 34: 32 Kinouchi K, Ichihara A, Sano M, Sun-Wada GH, Wada corresponding to the ‘handle’ region for nonproteolytic 301–307. Y, Kurauchi-Mito A, Bokuda K, Narita T, Oshima Y, activation of prorenin. J Clin Invest 2004; 114: 23 Nangaku M, Eckardt KU. Hypoxia and the HIF system Sakoda M, Tamai Y, Sato H, Fukuda K, Itoh H. The 1128–1135. in kidney disease. JMolMed2007; 85: 1325–1330. (pro)renin receptor/ATP6AP2 is essential for vacuolar 15 Takahashi H, Ichihara A, Kaneshiro Y, Inomata K, 24 Biswas KB, Nabi AH, Arai Y, Nakagawa T, Ebihara A, H+-ATPase assembly in murine cardiomyocytes. Circ Sakoda M, Takemitsu T, Nishiyama A, Itoh H. Regres- Ichihara A, Watanabe T, Inagami T, Suzuki F. Aliskiren Res 2010; 107: 30–34.

Hypertension Research