- Email: [email protected]
The clot thickens
co m m e nta r y
epitopes. That a moderate overexpression of the receptor in macula densa cells is responsible for a significant increase of COX-2 expression again suggests an extremely tight control of the effects of receptor activation in basal states. There is an increasing interest in the (pro)renin receptor, probably because it provides now a functional role for prorenin that was suspected long ago. The mechanism of control of receptor expression and desensitization is unknown so far. The elucidation of the molecular basis of the control of receptor activation in normal tissue, the study of the degree of receptor expression in pathological states, and the consequences of receptor overactivation now merit attention, and these studies would undoubtedly improve our knowledge of the tissue renin–angiotensin system. ACKNOWLEDGMENTS We are grateful to Jean-Marie Gasc for the in situ hybridization and immunohistochemistry pictures. REFERENCES 1. 2.
3.
4.
5.
6.
7.
8.
9.
620
Danser AH. Prorenin: back into the arena. Hypertension 2006; 47: 824–826. Nguyen G, Delarue F, Burcklé C et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002; 109: 1417–1427. Huang Y, Wongamorntham S, Kasting J et al. Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin IIindependent mechanisms. Kidney Int 2006; 69: 105–113. Suzuki F, Hayakawa M, Nakagawa T et al. Human prorenin has “gate and handle” regions for its non-proteolytic activation. J Biol Chem 2003; 278: 22217–22222. Ichihara A, Hayashi M, Kaneshiro Y et al. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin. J Clin Invest 2004; 114: 1128–1135. Ichihara A, Kaneshiro Y, Takemitsu T et al. Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension 2006; 47: 894–900. Satofuka S, Ichihara A, Nagai N et al. Suppression of ocular inflammation in endotoxin-induced uveitis by inhibiting nonproteolytic activation of prorenin. Invest Ophthalmol Vis Sci 2006; 47: 2686–2692. Ichihara A, Suzuki F, Nakagawa T et al. Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. J Am Soc Nephrol 2006; 17: 1950–1961. Kaneshiro Y, Ichihara A, Takemitsu T et al. Increased expression of cyclooxygenase-2 in the renal cortex of human prorenin receptor genetransgenic rats. Kidney Int 2006; 70: 641–646.
see original article on page 743
The clot thickens AB Fogo1 Vascular sclerosis has been linked to many risk factors, including smoking, family history, low birth weight, and hypertension. In interesting studies, Goforth et al. show an increased rate of mutations in thrombophilic molecules in patients with vascular sclerosis in renal biopsies, suggesting yet another mechanism. Kidney International (2006) 70, 620–621. doi:10.1038/sj.ki.5001721
The etiology and pathogenesis of vascular sclerosis have remained obscure, despite multiple levels of investigation. These studies have examined a variety of possible factors, including smoking, obesity, family history, and even low birth weight. A major focus has been on the well-known link between hypertension and accelerated vascular disease. However, vascular sclerotic lesions did not correlate with extent of hypertension in a biopsy study of presumed arterionephrosclerosis in African Americans.1 Further, the extent of sclerosis of arterioles and arteries did not correlate with the extent of global glomerulosclerosis. In a retrospective study examining biopsies done for clinical indications, vascular sclerosis and glomerulosclerosis were more severe in African Americans than in whites.2 However, in neither population was mean arterial pressure predictive of these morphologic lesions. In a large review of renal biopsies, Meyrier et al. found that degree of vascular sclerosis did not correlate with hypertension, and surprisingly, vascular sclerosis was even present at moderately severe levels in tubulointerstitial disease processes.3 Further, not all patients who exhibit hypertension show significant vascular lesions, particularly in the white population.4 These findings have pointed to the possibility of unrecognized factors other than blood pressure accounting 1Department of Pathology, Vanderbilt University
Medical Center, Nashville, Tennessee, USA Correspondence: AB Fogo, MCN C3310, Department of Pathology, Vanderbilt University Medial Center, Nashville, Tennessee 37232, USA. E-mail: [email protected]
for sclerosis of the vasculature. In the interesting study by Goforth et al.5 (this issue), the possibility of contribution of inherited thrombophilia to vascular sclerosis was investigated. They studied renal biopsies in adult patients with vascular sclerotic lesions, defined morphologically by intimal fibrosis and medial hypertrophy, excluding cases of immune complex glomerulonephritis. Patients were then further categorized as those with diabetes, hypertension, or both, those who smoked, and, finally, those with vascular sclerosis of unknown etiology. Genomic DNA extracted from remaining frozen tissue from these biopsies was then investigated to identify any mutations in the gene for factor V or for prothrombin, or mutation in a gene that causes hyperhomocysteinemia (methylenetetrahydrofolate reductase, MTHFR). Interestingly, among patients without known risk factors for vascular disease, such as diabetes, hypertension, or smoking, a significant proportion had mutations in one or more of these three genes. The small sample size precludes broad conclusions regarding other populations. However, the clustering of mutations in about half of the previously considered idiopathic vascular sclerosis group is of great interest. The contribution of factors governing hemostasis to acute thrombotic lesions and also vascular sclerosis has previously been recognized. Thus, plasminogen activator inhibitor-1 (PAI-1) is associated with increased risk for cardiovascular and renal disease. 6,7 PAI-1 levels are also regulated at the genetic level, with polymorphic variance Kidney International (2006) 70
co m m e nta r y
Thrombophilia
?
Low birth weight
Thrombosis
Vascular sclerosis PAI-1
Figure 1 | Proposed schema for hypothesized mechanisms of interactions between thrombophilia and vascular sclerosis. Thrombophilia may promote sclerosis directly by organization of thrombotic microangiopathic injury, or perhaps indirectly by resulting in adverse pregnancy outcomes, such as low birth weight, which has been linked to increased cardiovascular disease. Other factors influencing thrombosis, such as PAI-1, plasminogen activator inhibitor-1 (PAI-1), have direct effects to promote sclerosis by inhibiting breakdown of extracellular matrix and preventing clot lysis.
influencing plasma levels. The 4G/4G variant is associated with higher plasma PAI-1 levels than the 5G/5G variant; presumably this is related to the binding of 4G to a transcription activator and of 5G to an additional transcription repressor.8 Diabetic patients homozygous for 4G had increased macro- and microvascular complications, particularly when they were also homozygous for the D genotype of angiotensin-converting enzyme, which is associated with increased renin– angiotensin system activity. 9 As discussed by Goforth et al., 5 numerous additional factors, such as the complement-regulatory molecule factor H, and the coagulation cascade modifiers protein C, protein S, and anti-thrombin III, could also contribute to risk not only for thrombosis, but for subsequent vascular sclerosis. The link forged between prothrombotic factors and sclerosis may be direct, as is the case with PAI-1 (Figure 1). PAI-1 has several actions. It not only directly inhibits breakdown of fibrin by inhibiting formation of plasmin but also inhibits proteolysis by plasmin and plasminogen activators and other proteolytic molecules, thus promoting fibrosis and sclerosis. PAI-1 has, in addition, plasmin-independent effects to promote cell migration and fibrosis.6,7 For other
Kidney International (2006) 70
molecules, the link may be indirect (Figure 1). Inherited thrombophilias may have adverse influence on pregnancy outcomes.10 Whether they also could have more subtle effects on fetal development and growth and contribute to low birth weight, with subsequent increased risk for renal and cardiovascular disease, is not known. Another indirect link between thrombosis and sclerosis could be mediated by initial subtle endothelial dysfunction with or without localized thrombosis chronically resulting in a fibrotic reaction. Indeed, in the study by Goforth et al.,5 the latter mechanism is suggested in some patients by the electron microscopic findings demonstrating subendothelial expansion and new glomerular basement membrane formation, resulting in double contours, the classic morphologic appearance of a chronic thrombotic microangiopathy. The study by Goforth et al.5 importantly extends our previous observations linking such morphologic findings to a previous overt thrombotic condition or malignant hypertension, to patients in whom such underlying conditions were not clinically apparent and in whom no hypertension was yet present. In such patients, the results of Goforth et al.5 suggest that genetic factors modulating thrombosis have influenced the develop-
ment of vascular sclerosis. Whether the increased mutation rate of hemostatic factors also is present in other patient populations, such as African Americans, remains to be determined. The morphologic detection of vascular sclerosis, even in the absence of hypertension, may be an ominous sign for progressive renal dysfunction, in that compliance and reactivity of vessels may be compromised when the structure of the vessel is thus modified. Whether treatment specifically aimed at modifying activity of thrombophilic factors, rather than at decreasing blood pressure, would be particularly efficacious in ameliorating vascular sclerosis in this newly identified patient group, remains to be seen. Specific recognition of molecular defects contributing to vascular injury provides exciting new targets for treatment and intervention. REFERENCES 1.
Fogo A, Breyer JA, Smith MC et al. Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) trial. Kidney Int 1997; 51: 244–252. 2. Marcantoni C, Ma L-J, Federspiel C et al. Hypertensive nephrosclerosis in AfricanAmericans vs Caucasians. Kidney Int 2002; 62: 172–180. 3. Meyrier A, Simon P, Montseny JJ et al. Vascular nephropathies and nephrosclerosis: epidemiology and pathophysiology. Adv Nephrol Necker Hosp 1997; 26: 207–245. 4. Kincaid-Smith P, Whitworth JA. Hypertension and the kidney. In: Kincaid-Smith P, Whitworth JA (eds). The Kidney: A Clinicopathologic Study. Blackwell: Melbourne, 1987, p 131. 5. Goforth RL, Rennke H, Sethi S. Renal vascular sclerosis is associated with inherited thrombophilias. Kidney Int 2006; 70: 743–750. 6. Fogo AB. The role of angiotensin II and plasminogen activator inhibitor-1 in progressive glomerulosclerosis. Am J Kidney Dis 2000; 35: 179–188. 7. Eddy AA. Plasminogen activator inhibitor-1 and the kidney. Am J Physiol Renal Physiol 2002; 283: F209–F220. 8. Eriksson P, Kallin B, van ‘t Hooft FM et al. Allelespecific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851–1855. 9. Kimura H, Gejyo F, Suzuki Y et al. Polymorphisms of angiotensin converting enzyme and plasminogen activator inhibitor-1 genes in diabetes and macroangiopathy. Kidney Int 1998; 54: 1659–1669. 10. Abbate R, Sofi F, Gensini F et al. Thrombophilias as risk factors for disorders of pregnancy and fetal damage. Pathophysiol Haemost Thromb 2002; 32: 318–321.
621
epitopes. That a moderate overexpression of the receptor in macula densa cells is responsible for a significant increase of COX-2 expression again suggests an extremely tight control of the effects of receptor activation in basal states. There is an increasing interest in the (pro)renin receptor, probably because it provides now a functional role for prorenin that was suspected long ago. The mechanism of control of receptor expression and desensitization is unknown so far. The elucidation of the molecular basis of the control of receptor activation in normal tissue, the study of the degree of receptor expression in pathological states, and the consequences of receptor overactivation now merit attention, and these studies would undoubtedly improve our knowledge of the tissue renin–angiotensin system. ACKNOWLEDGMENTS We are grateful to Jean-Marie Gasc for the in situ hybridization and immunohistochemistry pictures. REFERENCES 1. 2.
3.
4.
5.
6.
7.
8.
9.
620
Danser AH. Prorenin: back into the arena. Hypertension 2006; 47: 824–826. Nguyen G, Delarue F, Burcklé C et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002; 109: 1417–1427. Huang Y, Wongamorntham S, Kasting J et al. Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin IIindependent mechanisms. Kidney Int 2006; 69: 105–113. Suzuki F, Hayakawa M, Nakagawa T et al. Human prorenin has “gate and handle” regions for its non-proteolytic activation. J Biol Chem 2003; 278: 22217–22222. Ichihara A, Hayashi M, Kaneshiro Y et al. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin. J Clin Invest 2004; 114: 1128–1135. Ichihara A, Kaneshiro Y, Takemitsu T et al. Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension 2006; 47: 894–900. Satofuka S, Ichihara A, Nagai N et al. Suppression of ocular inflammation in endotoxin-induced uveitis by inhibiting nonproteolytic activation of prorenin. Invest Ophthalmol Vis Sci 2006; 47: 2686–2692. Ichihara A, Suzuki F, Nakagawa T et al. Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. J Am Soc Nephrol 2006; 17: 1950–1961. Kaneshiro Y, Ichihara A, Takemitsu T et al. Increased expression of cyclooxygenase-2 in the renal cortex of human prorenin receptor genetransgenic rats. Kidney Int 2006; 70: 641–646.
see original article on page 743
The clot thickens AB Fogo1 Vascular sclerosis has been linked to many risk factors, including smoking, family history, low birth weight, and hypertension. In interesting studies, Goforth et al. show an increased rate of mutations in thrombophilic molecules in patients with vascular sclerosis in renal biopsies, suggesting yet another mechanism. Kidney International (2006) 70, 620–621. doi:10.1038/sj.ki.5001721
The etiology and pathogenesis of vascular sclerosis have remained obscure, despite multiple levels of investigation. These studies have examined a variety of possible factors, including smoking, obesity, family history, and even low birth weight. A major focus has been on the well-known link between hypertension and accelerated vascular disease. However, vascular sclerotic lesions did not correlate with extent of hypertension in a biopsy study of presumed arterionephrosclerosis in African Americans.1 Further, the extent of sclerosis of arterioles and arteries did not correlate with the extent of global glomerulosclerosis. In a retrospective study examining biopsies done for clinical indications, vascular sclerosis and glomerulosclerosis were more severe in African Americans than in whites.2 However, in neither population was mean arterial pressure predictive of these morphologic lesions. In a large review of renal biopsies, Meyrier et al. found that degree of vascular sclerosis did not correlate with hypertension, and surprisingly, vascular sclerosis was even present at moderately severe levels in tubulointerstitial disease processes.3 Further, not all patients who exhibit hypertension show significant vascular lesions, particularly in the white population.4 These findings have pointed to the possibility of unrecognized factors other than blood pressure accounting 1Department of Pathology, Vanderbilt University
Medical Center, Nashville, Tennessee, USA Correspondence: AB Fogo, MCN C3310, Department of Pathology, Vanderbilt University Medial Center, Nashville, Tennessee 37232, USA. E-mail: [email protected]
for sclerosis of the vasculature. In the interesting study by Goforth et al.5 (this issue), the possibility of contribution of inherited thrombophilia to vascular sclerosis was investigated. They studied renal biopsies in adult patients with vascular sclerotic lesions, defined morphologically by intimal fibrosis and medial hypertrophy, excluding cases of immune complex glomerulonephritis. Patients were then further categorized as those with diabetes, hypertension, or both, those who smoked, and, finally, those with vascular sclerosis of unknown etiology. Genomic DNA extracted from remaining frozen tissue from these biopsies was then investigated to identify any mutations in the gene for factor V or for prothrombin, or mutation in a gene that causes hyperhomocysteinemia (methylenetetrahydrofolate reductase, MTHFR). Interestingly, among patients without known risk factors for vascular disease, such as diabetes, hypertension, or smoking, a significant proportion had mutations in one or more of these three genes. The small sample size precludes broad conclusions regarding other populations. However, the clustering of mutations in about half of the previously considered idiopathic vascular sclerosis group is of great interest. The contribution of factors governing hemostasis to acute thrombotic lesions and also vascular sclerosis has previously been recognized. Thus, plasminogen activator inhibitor-1 (PAI-1) is associated with increased risk for cardiovascular and renal disease. 6,7 PAI-1 levels are also regulated at the genetic level, with polymorphic variance Kidney International (2006) 70
co m m e nta r y
Thrombophilia
?
Low birth weight
Thrombosis
Vascular sclerosis PAI-1
Figure 1 | Proposed schema for hypothesized mechanisms of interactions between thrombophilia and vascular sclerosis. Thrombophilia may promote sclerosis directly by organization of thrombotic microangiopathic injury, or perhaps indirectly by resulting in adverse pregnancy outcomes, such as low birth weight, which has been linked to increased cardiovascular disease. Other factors influencing thrombosis, such as PAI-1, plasminogen activator inhibitor-1 (PAI-1), have direct effects to promote sclerosis by inhibiting breakdown of extracellular matrix and preventing clot lysis.
influencing plasma levels. The 4G/4G variant is associated with higher plasma PAI-1 levels than the 5G/5G variant; presumably this is related to the binding of 4G to a transcription activator and of 5G to an additional transcription repressor.8 Diabetic patients homozygous for 4G had increased macro- and microvascular complications, particularly when they were also homozygous for the D genotype of angiotensin-converting enzyme, which is associated with increased renin– angiotensin system activity. 9 As discussed by Goforth et al., 5 numerous additional factors, such as the complement-regulatory molecule factor H, and the coagulation cascade modifiers protein C, protein S, and anti-thrombin III, could also contribute to risk not only for thrombosis, but for subsequent vascular sclerosis. The link forged between prothrombotic factors and sclerosis may be direct, as is the case with PAI-1 (Figure 1). PAI-1 has several actions. It not only directly inhibits breakdown of fibrin by inhibiting formation of plasmin but also inhibits proteolysis by plasmin and plasminogen activators and other proteolytic molecules, thus promoting fibrosis and sclerosis. PAI-1 has, in addition, plasmin-independent effects to promote cell migration and fibrosis.6,7 For other
Kidney International (2006) 70
molecules, the link may be indirect (Figure 1). Inherited thrombophilias may have adverse influence on pregnancy outcomes.10 Whether they also could have more subtle effects on fetal development and growth and contribute to low birth weight, with subsequent increased risk for renal and cardiovascular disease, is not known. Another indirect link between thrombosis and sclerosis could be mediated by initial subtle endothelial dysfunction with or without localized thrombosis chronically resulting in a fibrotic reaction. Indeed, in the study by Goforth et al.,5 the latter mechanism is suggested in some patients by the electron microscopic findings demonstrating subendothelial expansion and new glomerular basement membrane formation, resulting in double contours, the classic morphologic appearance of a chronic thrombotic microangiopathy. The study by Goforth et al.5 importantly extends our previous observations linking such morphologic findings to a previous overt thrombotic condition or malignant hypertension, to patients in whom such underlying conditions were not clinically apparent and in whom no hypertension was yet present. In such patients, the results of Goforth et al.5 suggest that genetic factors modulating thrombosis have influenced the develop-
ment of vascular sclerosis. Whether the increased mutation rate of hemostatic factors also is present in other patient populations, such as African Americans, remains to be determined. The morphologic detection of vascular sclerosis, even in the absence of hypertension, may be an ominous sign for progressive renal dysfunction, in that compliance and reactivity of vessels may be compromised when the structure of the vessel is thus modified. Whether treatment specifically aimed at modifying activity of thrombophilic factors, rather than at decreasing blood pressure, would be particularly efficacious in ameliorating vascular sclerosis in this newly identified patient group, remains to be seen. Specific recognition of molecular defects contributing to vascular injury provides exciting new targets for treatment and intervention. REFERENCES 1.
Fogo A, Breyer JA, Smith MC et al. Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) trial. Kidney Int 1997; 51: 244–252. 2. Marcantoni C, Ma L-J, Federspiel C et al. Hypertensive nephrosclerosis in AfricanAmericans vs Caucasians. Kidney Int 2002; 62: 172–180. 3. Meyrier A, Simon P, Montseny JJ et al. Vascular nephropathies and nephrosclerosis: epidemiology and pathophysiology. Adv Nephrol Necker Hosp 1997; 26: 207–245. 4. Kincaid-Smith P, Whitworth JA. Hypertension and the kidney. In: Kincaid-Smith P, Whitworth JA (eds). The Kidney: A Clinicopathologic Study. Blackwell: Melbourne, 1987, p 131. 5. Goforth RL, Rennke H, Sethi S. Renal vascular sclerosis is associated with inherited thrombophilias. Kidney Int 2006; 70: 743–750. 6. Fogo AB. The role of angiotensin II and plasminogen activator inhibitor-1 in progressive glomerulosclerosis. Am J Kidney Dis 2000; 35: 179–188. 7. Eddy AA. Plasminogen activator inhibitor-1 and the kidney. Am J Physiol Renal Physiol 2002; 283: F209–F220. 8. Eriksson P, Kallin B, van ‘t Hooft FM et al. Allelespecific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851–1855. 9. Kimura H, Gejyo F, Suzuki Y et al. Polymorphisms of angiotensin converting enzyme and plasminogen activator inhibitor-1 genes in diabetes and macroangiopathy. Kidney Int 1998; 54: 1659–1669. 10. Abbate R, Sofi F, Gensini F et al. Thrombophilias as risk factors for disorders of pregnancy and fetal damage. Pathophysiol Haemost Thromb 2002; 32: 318–321.
621