Hypertension Research (2011) 34, 289–291 & 2011 The Japanese Society of Hypertension All rights reserved 0916-9636/11 $32.00 www.nature.com/hr 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.