[Frontiers in Bioscience S3, 1478-1485, June 1, 2011]

Possible involvement of the (pro)renin receptor-dependent system in the development of insulin resistance

Kazi Rafiq1, Hirofumi Hitomi1, Daisuke Nakano1, Atsuhiro Ichihara2, Akira Nishiyama1

1Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan, 2Anti-Aging Medicine and Endocrinology and Internal Medicine, Keio University School of Medicine, Tokyo, Japan


1. Abstract
2. Introduction
3. RAS and Insulin Resistance
4. Insulin Resistance and the (Pro)renin Receptor-dependent System
5. Clinical Studies
6. Conclusions
7. References


It is widely acknowledged that activation of the renin-angiotensin system impairs insulin sensitivity. Pharmacological inhibition of the (pro)renin receptor-dependent system has shown beneficial effects in diabetic nephropathy, retinopathy and hypertensive cardiac damage in animal models. Previously, we showed that fructose feeding stimulated nonproteolytic activation of prorenin and subsequent production of angiotensin II in skeletal muscle in rats, and that inhibition of the (pro)renin receptor-dependent system improved the development of fructose feeding-induced insulin resistance. In addition, our current preliminary study suggests that local angiotensin II generation in skeletal muscle and adipose tissues induced by nonproteolytic activation of prorenin is involved in the development of spontaneous insulin resistance in type 2 diabetic rats. In this review, we will briefly summarize the possible contribution of the (pro)renin receptor-dependent system to the pathogenesis of insulin resistance, with a focus on how the nonproteolytic activation of prorenin contributes to the development of insulin resistance.


A growing body of evidence suggests that activation of the renin-angiotensin system (RAS) impairs insulin sensitivity (1), and that hyperinsulinemia and insulin resistance promote the development of cardiovascular disorders (2, 3). In addition, clinical studies have shown that treatments with RAS inhibitors, such as angiotensin (Ang)-converting enzyme (ACE) inhibitors (4), Ang II type 1 receptor blockers (ARBs) (5) and a direct renin inhibitor (DRI) (6), prevent the development of insulin resistance in hypertensive patients, indicating that ACE, Ang II and renin contribute to the development of insulin resistance. On the other hand, it is also acknowledged that tissue RAS, such as the intrarenal Ang II levels, are regulated in a manner distinct from the systemic RAS (7). However, the mechanisms by which tissue RAS is activated during the development of insulin resistance are still unclear.

Prorenin, the enzymatically inactive precursor of renin, is expressed in various tissues (8), and has an amino-terminal prosegment that is thought to cover the enzymatic cleft and obstruct access to its substrate, angiotensinogen. Prorenin is also known to be activated without catalytic conversion into mature renin via the (pro)renin receptor (9). The activated prorenin can generate Ang I locally, thereby accelerating the subsequent tissue production of Ang II (8). Interestingly, mature renin can also bind to (pro)renin receptor, and the amount of Ang I generated by receptor-bound renin dramatically exceeds that by unbound renin (8), suggesting that activation of both renin and prorenin is facilitated by binding to (pro)renin receptor. The locally produced Ang II acts as an autocrine/paracrine factor and induces local actions that are independent of the systemic actions induced by circulating Ang II. Ichihara et al. demonstrated that inhibition of the nonproteolytic activation of prorenin with a decoy peptide containing the handle region of the prorenin prosegment decreases Ang II formation in the heart (10) and renal tissues of hypertensive rats (11) and in the renal tissues of type 1 diabetic rats (12) without large changes in the systemic RAS. Moreover, fructose feeding induces nonproteolytic activation of prorenin and subsequent Ang II production in skeletal muscle in rats (13). Inhibition of these changes by the handle region peptide (HRP) may be involved in the attenuation of fructose feeding-induced insulin resistance. However, the roles of (pro)renin receptor in the development of insulin resistance are poorly understood. In this short review, we will briefly summarize the possible contribution of the (pro)renin receptor-dependent system to the pathogenesis of insulin resistance, with a focus on how the nonproteolytic activation of prorenin contributes to the development of spontaneous insulin resistance.


It is widely acknowledged that ACE inhibitors and ARBs blunt the progression of type 2 diabetic nephropathy (4, 5) and reduce the incidence of new onset of type 2 diabetes mellitus (14, 15) in humans. Previous studies have also shown that RAS inhibition by ACE inhibitors or ARBs improves glucose intolerance in type 2 diabetic mice (16, 17). The beneficial effects of ACE inhibitors and ARBs indicate the importance of the RAS in the pathogenesis of type 2 diabetes and its complications. In addition, recent studies have reported beneficial effects of a DRI on insulin resistance (18-21). Studies on db/db mice revealed that the DRI, aliskiren, exhibits organ-protective effects by improving insulin resistance and lipid abnormalities, as well as, having anti-fibrotic effects on target organs (18) and ameliorating pancreatic injury (19). These studies raise the interesting possibility that renin may be linked to insulin resistance and lipid abnormalities in type 2 diabetes mellitus. Recently, Iwai et al. (20) have demonstrated that aliskiren improves the impairment of plasma glucose in the oral glucose tolerance test (OGTT) and increases the response to insulin injection in the insulin tolerance test in diabetic KKAy mice. Aliskiren also decreases oxidative stress and inflammatory markers in insulin-sensitive organs such as skeletal muscle and adipose tissues. In addition, aliskiren can potentiate adipocyte differentiation, which may be involved in the improvement of adipocyte dysfunction and insulin sensitivity (20). Moreover, aliskiren enhances insulin secretion by restoring β cells in pancreatic islets through a reduction in oxidative stress (20). A recent study by Lastra et al. (21) showed that renin inhibition by aliskiren improves systemic insulin sensitivity, skeletal muscle insulin metabolic signaling, and glucose transport in Ren2 rats. These beneficial effects of aliskiren on insulin resistance are qualitatively similar to the effect of ARBs as previously reported by the same group (22). These in vivo experiments using aliskiren revealed that the DRI has a protective effect for insulin resistance and diabetic complications.


Diabetic patients have relatively low circulating plasma renin activity (23, 24). High levels of prorenin, but low circulating plasma renin activity, are closely associated with the severity of diabetic complications (23, 24). The possible contribution of the (pro)renin receptor-dependent system to the development of insulin resistance are unclear, although insulin resistance and diabetic complications were improved by renin or prorenin inhibition using aliskiren or the HRP, respectively (6, 12). We previously suggested that the (pro)renin receptor-dependent system is activated in skeletal muscle and contributes to the development of insulin resistance in a fructose feeding-induced insulin-resistant rat model (13). HRP treatment markedly improved the glucose intolerance and caused less increase in the insulin level in response to oral glucose administration in high-fructose-fed rats. Importantly, fructose feeding augmented nonproteolytic activation of prorenin in skeletal muscle and the increased Ang II contents in skeletal muscle are also attenuated by HRP treatment. These findings indicate that nonproteolytic activation of prorenin is involved in RAS activation of skeletal muscle during the development of insulin resistance in high-fructose-fed rats. Although these observations indicate that local RAS activation mediated by (pro)renin receptors is involved in insulin resistance induced by fructose feeding, it is still unclear whether nonproteolytic activation of prorenin contributes to the development of spontaneous insulin resistance in type 2 diabetes mellitus.

Therefore, we designed our current preliminary study to test the hypothesis that nonproteolytic activation of prorenin is involved to the development of spontaneous insulin resistance. Six-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) and non-diabetic control male Long-Evans Tokushima Otsuka (LETO) rats (Otsuka Pharmaceutical, Tokushima, Japan) were maintained under a controlled temperature (24 � 2�C) and humidity (55 � 5%), with a 12-h/12-h light/dark cycle. Throughout the experimental period, the rats had free access to laboratory rat chow and tap water. OLETF rats exhibit a prediabetic stage characterized by postprandial hyperglycemia and insulin resistance from 10 to 20 weeks of age (25). Therefore, we harvested the tissues at 15 weeks of age. The OGTT and hyperinsulinemic-euglycemic clamp study were performed after overnight fasting to evaluate the insulin sensitivity, as previously described (13). Immunohistochemical staining with an anti-rat prorenin gate region antibody for activated prorenin was performed as previously described (13). Ang II contents in the soleus muscle and adipose tissues were measured by a radioimmunoassay, as previously described (26). In this preliminary study, we found that 15-week-old OLETF rats exhibited glucose intolerance as assessed by the OGTT. OLETF rats showed marked increases in the blood glucose level and area under the curve in response to oral glucose loading during the OGTT (Figure 1). OLETF rats also showed a marked increase in the plasma insulin level compared with age-matched LETO rats (Figure 1). Furthermore, the whole body insulin sensitivity was assessed by the hyperinsulinemic-euglycemic clamp study. OLETF rats showed a significantly lower glucose infusion rate than LETO rats (0.90 � 0.15 vs. 1.41 � 0.09 mg/kg/hour, P<0.05, n=4 for each). Interestingly, OLETF rats showed nonproteolytic activation of prorenin in the soleus muscle and adipose tissues (Figure 2) as assessed by immunohistochemical staining of the gate region of prorenin, which is not accessible by its specific antibodies until it is loosened from the active site cleft, representing the phenomenon called nonproteolytic activation of prorenin (11). In contrast, the mRNA expression level of the (pro)renin receptor were similar in OLETF and LETO rats (Figure 2). OLETF rats showed augmented Ang II contents in the soleus muscle and adipose tissues compared with LETO rats (Figure 3). These findings indicate that nonproteolytic activation of prorenin participates in the development of spontaneous insulin resistance in type 2 diabetic rats through local (skeletal muscle and adipose tissues) RAS activation, at least in part (Figure 4). Further studies are needed to clarify the precise molecular mechanism responsible for the prorenin-induced insulin resistance via the (pro)renin receptor in type 2 diabetic rats.


Emerging clinical evidence indicates that ACE inhibitors and ARBs reduce cardiovascular and renal complications in diabetes and new onset of diabetes (4, 15), and these agents are now considered as a first-line therapies for the treatment of hypertensive patients with type 2 diabetes mellitus (27-29). These effects of ACE inhibitors and ARBs have been explained by their hemodynamic effects, such as improved delivery of insulin and glucose to peripheral skeletal muscle, and nonhemodynamic effects, such as direct effects on glucose transport and insulin signaling pathways, all of which decrease insulin resistance (30, 31). Indeed, clinical studies showed that treatment with ARBs or ACE inhibitors improves insulin resistance in hypertensive patients (32).

Aliskiren is a novel orally effective DRI, and its RAS-blocking pharmacological actions are different from those of conventional RAS blockers (33). For instance, aliskiren can bind not only to the free and receptor-bound form of renin, but also to receptor bound prorenin, which displays kinetics similar to active renin, and thus inhibit their renin activity (34). Clinical studies have suggested that aliskiren not only lowers blood pressure in hypertensive patients (35) but also attenuates cardiovascular and renal injuries as well as pancreatic injuries in type 2 diabetes mellitus (36). A recent clinical study, entitled "Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID)", showed that aliskiren combined with losartan has significant anti-proteinuric effects that are independent of its blood pressure-lowering effects in patients with hypertension and diabetic nephropathy (6). These results suggest beneficial effects of RAS intervention by DRI administration on hypertensive and diabetic complications. Another recent clinical study found that women with polycystic ovarian syndrome show insulin resistance and increased serum renin levels (37). In addition, it has proposed that prorenin is a useful marker of diabetic microvascular complications (23) and retinopathy of prematurity (38). These data indicate a possible link between renin activation and insulin resistance. Further clinical studies are required to elucidate the benefits of the protective effects of the DRI on insulin resistance and diabetic complications. However, it remains unclear whether these effects of DRI are mediated through the inhibition of local Ang II generation by (pro)renin receptor-dependent system.


In this review, we have discussed the possible roles of the (pro)renin receptor-dependent system in the development of insulin resistance. Our preliminary data indicate that the (pro)renin receptor-dependent system may be involved, at least in part, in the development of insulin resistance through local production of Ang II in type 2 diabetes mellitus.


1. Henriksen, E. J.: Improvement of insulin sensitivity by antagonism of the renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol, 293, R974-80 (2007)
doi: 10.​1152/​ajpregu.​00147.​2007

PMID: 17581838

2. Mottillo, S., K. B. Filion, J. Genest, L. Joseph, L. Pilote, P. Poirier, S. Rinfret, E. L. Schiffrin & M. J. Eisenberg: The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol, 56, 1113-32 (2010)
doi: 10.1016/j.jacc.2010.05.034

PMID: 20863953

3. McFarlane, S. I., M. Banerji & J. R. Sowers: Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab, 86, 713-8 (2001)

PMID: 11158035

4. Yusuf, S., P. Sleight, J. Pogue, J. Bosch, R. Davies & G. Dagenais: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med, 342, 145-53 (2000)

PMID: 10639539

5. Brenner, B. M., M. E. Cooper, D. de Zeeuw, W. F. Keane, W. E. Mitch, H. H. Parving, G. Remuzzi, S. M. Snapinn, Z. Zhang & S. Shahinfar: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med, 345, 861-9 (2001)

PMID: 11565518

6. Parving, H. H., F. Persson, J. B. Lewis, E. J. Lewis & N. K. Hollenberg: Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med, 358, 2433-46 (2008)
doi: 10.1056/NEJMoa0708379

PMID: 18525041

7. Kobori, H., M. Nangaku, L. G. Navar & A. Nishiyama: The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev, 59, 251-87 (2007)

PMID: 17878513

8. Nguyen, G., F. Delarue, C. Burckle, L. Bouzhir, T. Giller & J. D. Sraer: Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest, 109, 1417-27 (2002)
doi: 10.1172/JCI14276

PMID: 12045255

9. Suzuki, F., M. Hayakawa, T. Nakagawa, U. M. Nasir, A. Ebihara, A. Iwasawa, Y. Ishida, Y. Nakamura & K. Murakami: Human prorenin has "gate and handle" regions for its non-proteolytic activation. J Biol Chem, 278, 22217-22 (2003)
doi: 10.1074/jbc.M302579200

PMID: 12684512

10. Ichihara, A., Y. Kaneshiro, T. Takemitsu, M. Sakoda, F. Suzuki, T. Nakagawa, A. Nishiyama, T. Inagami & M. Hayashi: Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension, 47, 894-900 (2006)
doi: 10.1161/01.HYP.0000215838.48170.0b

PMID: 16585419

11. Ichihara, A., Y. Kaneshiro, T. Takemitsu, M. Sakoda, T. Nakagawa, A. Nishiyama, H. Kawachi, F. Shimizu & T. Inagami: Contribution of nonproteolytically activated prorenin in glomeruli to hypertensive renal damage. J Am Soc Nephrol, 17, 2495-503 (2006)doi: 10.1681/ASN.2005121278

PMID: 16885412

12. Ichihara, A., M. Hayashi, Y. Kaneshiro, F. Suzuki, T. Nakagawa, Y. Tada, Y. Koura, A. Nishiyama, H. Okada, M. N. Uddin, A. H. Nabi, Y. Ishida, T. Inagami & T. Saruta: Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin. J Clin Invest, 114, 1128-35 (2004)
doi: 10.1172/JCI21398

PMID: 15489960

13. Nagai, Y., A. Ichihara, D. Nakano, S. Kimura, N. Pelisch, Y. Fujisawa, H. Hitomi, N. Hosomi, H. Kiyomoto, M. Kohno, H. Ito & A. Nishiyama: Possible contribution of the non-proteolytic activation of prorenin to the development of insulin resistance in fructose-fed rats. Exp Physiol, 94, 1016-23 (2009)
doi: 10.1113/expphysiol.2009.048108

PMID: 19502292

14. Abuissa, H., P. G. Jones, S. P. Marso & J. H. O'Keefe, Jr.: Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. J Am Coll Cardiol, 46, 821-6 (2005)doi: 10.1016/j.jacc.2005.05.051

PMID: 16139131

15. Dahlof, B., R. B. Devereux, S. E. Kjeldsen, S. Julius, G. Beevers, U. de Faire, F. Fyhrquist, H. Ibsen, K. Kristiansson, O. Lederballe-Pedersen, L. H. Lindholm, M. S. Nieminen, P. Omvik, S. Oparil & H. Wedel: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet, 359, 995-1003 (2002)
doi: 10.1016/S0140-6736(02)08089-3

PMID: 11937178

16. Shiuchi, T., T. X. Cui, L. Wu, H. Nakagami, Y. Takeda-Matsubara, M. Iwai & M. Horiuchi: ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO. Hypertension, 40, 329-34 (2002)
doi: 10.1161/01.HYP.0000028979.98877.0C

PMID: 12215475

17. Shiuchi, T., M. Iwai, H. S. Li, L. Wu, L. J. Min, J. M. Li, M. Okumura, T. X. Cui & M. Horiuchi: Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice. Hypertension, 43, 1003-10 (2004)
doi: 10.1161/01.HYP.0000125142.41703.64

PMID: 15037562

18. Kang, Y. S., M. H. Lee, H. K. Song, Y. Y. Hyun, J. J. Cha, G. J. Ko, S. H. Kim, J. E. Lee, J. Y. Han & D. R. Cha: Aliskiren improves insulin resistance and ameliorates diabetic vascular complications in db/db mice. Nephrol Dial Transplant (2010)
doi: 10.1093/ndt/gfq579

PMID: 20921292

19. Dong, Y. F., L. Liu, K. Kataoka, T. Nakamura, M. Fukuda, Y. Tokutomi, H. Nako, H. Ogawa & S. Kim-Mitsuyama: Aliskiren prevents cardiovascular complications and pancreatic injury in a mouse model of obesity and type 2 diabetes. Diabetologia, 53, 180-91 (2010)
doi: 10.1007/s00125-009-1575-5

PMID: 19894030

20. Iwai, M., H. Kanno, Y. Tomono, S. Inaba, I. Senba, M. Furuno, M. Mogi & M. Horiuchi: Direct renin inhibition improved insulin resistance and adipose tissue dysfunction in type 2 diabetic KK-A(y) mice. J Hypertens, 28, 1471-81 (2010)
doi: 10.1097/HJH.0b013e32833bc420

PMID: 20543712

21. Lastra, G., J. Habibi, A. T. Whaley-Connell, C. Manrique, M. R. Hayden, J. Rehmer, K. Patel, C. Ferrario & J. R. Sowers: Direct renin inhibition improves systemic insulin resistance and skeletal muscle glucose transport in a transgenic rodent model of tissue renin overexpression. Endocrinology, 150, 2561-8 (2009)
doi: 10.1210/en.2008-1391

PMID: 19246535

22. Tomono, Y., M. Iwai, S. Inaba, M. Mogi & M. Horiuchi: Blockade of AT1 receptor improves adipocyte differentiation in atherosclerotic and diabetic models. Am J Hypertens, 21, 206-12 (2008)

PMID: 18188158

23. Luetscher, J. A., F. B. Kraemer, D. M. Wilson, H. C. Schwartz & M. Bryer-Ash: Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications. N Engl J Med, 312, 1412-7 (1985)

PMID: 3887168

24. Wilson, D. M. & J. A. Luetscher: Plasma prorenin activity and complications in children with insulin-dependent diabetes mellitus. N Engl J Med, 323, 1101-6 (1990)

PMID: 2215578

25. Kawano, K., T. Hirashima, S. Mori, Y. Saitoh, M. Kurosumi & T. Natori: Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes, 41, 1422-8 (1992)

PMID: 1397718

26. Nishiyama, A., D. M. Seth & L. G. Navar: Renal interstitial fluid concentrations of angiotensins I and II in anesthetized rats. Hypertension, 39, 129-34 (2002)

PMID: 11799091

27. Buse, J. B., H. N. Ginsberg, G. L. Bakris, N. G. Clark, F. Costa, R. Eckel, V. Fonseca, H. C. Gerstein, S. Grundy, R. W. Nesto, M. P. Pignone, J. Plutzky, D. Porte, R. Redberg, K. F. Stitzel & N. J. Stone: Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation, 115, 114-26 (2007)
doi: 10.1161/CIRCULATIONAHA.106.179294

PMID: 17192512

28. Mancia, G., G. De Backer, A. Dominiczak, R. Cifkova, R. Fagard, G. Germano, G. Grassi, A. M. Heagerty, S. E. Kjeldsen, S. Laurent, K. Narkiewicz, L. Ruilope, A. Rynkiewicz, R. E. Schmieder, H. A. Boudier, A. Zanchetti, A. Vahanian, J. Camm, R. De Caterina, V. Dean, K. Dickstein, G. Filippatos, C. Funck-Brentano, I. Hellemans, S. D. Kristensen, K. McGregor, U. Sechtem, S. Silber, M. Tendera, P. Widimsky, J. L. Zamorano, S. Erdine, W. Kiowski, E. Agabiti-Rosei, E. Ambrosioni, L. H. Lindholm, M. Viigimaa, S. Adamopoulos, E. Agabiti-Rosei, E. Ambrosioni, V. Bertomeu, D. Clement, S. Erdine, C. Farsang, D. Gaita, G. Lip, J. M. Mallion, A. J. Manolis, P. M. Nilsson, E. O'Brien, P. Ponikowski, J. Redon, F. Ruschitzka, J. Tamargo, P. van Zwieten, B. Waeber & B. Williams: 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens, 25, 1105-87 (2007)doi:10.1097/HJH.0b013e3282f0580f

PMID: 17563527

29. Ogihara, T., K. Kikuchi, H. Matsuoka, T. Fujita, J. Higaki, M. Horiuchi, Y. Imai, T. Imaizumi, S. Ito, H. Iwao, K. Kario, Y. Kawano, S. Kim-Mitsuyama, G. Kimura, H. Matsubara, H. Matsuura, M. Naruse, I. Saito, K. Shimada, K. Shimamoto, H. Suzuki, S. Takishita, N. Tanahashi, T. Tsuchihashi, M. Uchiyama, S. Ueda, H. Ueshima, S. Umemura, T. Ishimitsu & H. Rakugi: The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009). Hypertens Res, 32, 3-107 (2009)

PMID: 19300436

30. Suzuki, K., O. Nakagawa & Y. Aizawa: Improved early-phase insulin response after candesartan treatment in hypertensive patients with impaired glucose tolerance. Clin Exp Hypertens, 30, 309-14 (2008)

PMID: 18633754

31. McFarlane, S. I., A. Kumar & J. R. Sowers: Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease. Am J Cardiol, 91, 30H-37H (2003)

PMID: 12818733

32. Iimura, O., K. Shimamoto, K. Matsuda, A. Masuda, H. Takizawa, K. Higashiura, Y. Miyazaki, A. Hirata, N. Ura & M. Nakagawa: Effects of angiotensin receptor antagonist and angiotensin converting enzyme inhibitor on insulin sensitivity in fructose-fed hypertensive rats and essential hypertensives. Am J Hypertens, 8, 353-7 (1995)

PMID: 7619347

33. Jensen, C., P. Herold & H. R. Brunner: Aliskiren: the first renin inhibitor for clinical treatment. Nat Rev Drug Discov, 7, 399-410 (2008)

PMID: 18340340

34. Biswas, K. B., A. H. Nabi, Y. Arai, T. Nakagawa, A. Ebihara, A. Ichihara, T. Watanabe, T. Inagami & F. Suzuki: Aliskiren binds to renin and prorenin bound to (pro)renin receptor in vitro. Hypertens Res, 33, 1053-9 (2010)

PMID: 20664543

35. Gradman, A. H., R. E. Schmieder, R. L. Lins, J. Nussberger, Y. Chiang & M. P. Bedigian: Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation, 111, 1012-8 (2005)

PMID: 15723979

36. Imanishi, T., H. Tsujioka, H. Ikejima, A. Kuroi, S. Takarada, H. Kitabata, T. Tanimoto, Y. Muragaki, S. Mochizuki, M. Goto, K. Yoshida & T. Akasaka: Renin inhibitor aliskiren improves impaired nitric oxide bioavailability and protects against atherosclerotic changes. Hypertension, 52, 563-72 (2008)

PMID: 18645051

37. Diamanti-Kandarakis, E., F. N. Economou, S. Livadas, E. Tantalaki, C. Piperi, A. G. Papavassiliou & D. Panidis: Hyperreninemia characterizing women with polycystic ovary syndrome improves after metformin therapy. Kidney Blood Press Res, 32, 24-31 (2009)

PMID: 19212122

38. Yokota, H., T. Nagaoka, F. Mori, T. Hikichi, H. Hosokawa, H. Tanaka, Y. Ishida, F. Suzuki & A. Yoshida: Prorenin levels in retinopathy of prematurity. Am J Ophthalmol, 143, 531-3 (2007)

PMID: 17317409

Key Words: Prorenin, (Pro)Renin Receptor, Insulin Resistance, Skeletal Muscle, Diabetes Mellitus, Review

Send correspondence to: Hirofumi Hitomi, Department of Pharmacology, Faculty of Medicine, Kagawa University; 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793, Japan, Tel: 81-87-891-2125, Fax: 81-87-891-2126, E-mail: hitomi@kms.ac.jp