Des Disease Status and Steroid Responsivenoess in Idiopathic Nephrotic Syndrome
Depend on ACE I/D Gene Polymorphism? A Study from South India
Umme N. Mahwish,
G. Suman Latha,
D. Sree Bhushan Raju
Idiopathic Nephrotic Syndrome (INS) is a malfunction of the kidney glomerular filter that leads to proteinuria, hypoalbuminemia, edema and renal failure. The cause of proteinuria in INS is an injury to the function or structure of glomerular filtration barrier. The present study addresses the role of I/D gene polymorphism of Angiotensin Converting Enzyme (ACE), a pleiotropic molecule on the susceptibility, progression and steroid response variation of INS in South Indian population. For this study, a total of 418 subjects were recruited; 218 clinically proven cases of INS without any secondary reasons for renal problems and 200 healthy controls. Association of ACE I/D gene polymorphism with disease susceptibility, renal histological findings and response to steroid treatment was evaluated. Three significant observations were made (1) Elevated frequency of DD in patients compared to controls (37.6% vs. 17.5%, p = 0.0001) (2) Higher I allele frequency in milder form than in severe form of INS (0.52 vs. 0.29, p = 0.0001) and (3) Patients with ID genotype were 3 times more resistant to steroid treatment compared to other genotypes (z-value = 3.45, p<0.0006). ACE I/D genotypes significantly influences the susceptibility, progression and drug response variation. This information may help the clinicians to predict the course of disease and to identify individuals with better prognosis to standard steroid treatment. In order to delineate the role of different genotypes on the above aspects, its influence at the physiological level is to be studied with large sample in different ethnic groups. This is the first Indian study pertaining to primary nephrotic syndrome dealing with ACE influence on susceptibility, severity and steroid response cumulatively.
to cite this article:
Wali Unnisa, Asra Tabassum, Umme N. Mahwish, G. Suman Latha, D. Sree Bhushan Raju and Parveen Jahan, 2012. Des Disease Status and Steroid Responsivenoess in Idiopathic Nephrotic Syndrome
Depend on ACE I/D Gene Polymorphism? A Study from South India. Asian Journal of Biological Sciences, 5: 148-156.
Received: January 08, 2012;
Accepted: February 20, 2012;
Published: May 17, 2012
Kidneys excrete waste products of metabolism and play an important role in
maintaining the homeostasis by regulating the body water and solute balance.
In addition they also participate in endocrine regulation (Al-Omireeni
et al., 2011). Chronic Kidney Disease (CKD) is the major cause of
morbidity, mortality and represents an important health problem worldwide. In
addition to medical problem, CKD is a huge social and economic problem that
needs to be addressed as the cost of dialysis and kidney transplantation is
increasing over time (Mortazavi and Rafiee, 2010). Idiopathic
Nephrotic Syndrome (INS) is a malfunction of the kidney glomerular filter and
is one of the commonest causes of renal problems in children encountered by
nephrologists (Braden et al., 2000). The characteristic
features of INS are heavy proteinuria (>40 mg m-2 h-1),
hypoalbuminemia (<2.5 g dL-1), edema and hyperlipidemia (Saber
et al., 2007). The cause of proteinuria is due to injury to the function
or structure of glomerular filtration barrier. The estimated annual incidence
of INS ranges from 2-7 per 100,000 children and prevalence from 12-16 per 100,000
worldwide. There is epidemiological evidence of a higher incidence of INS in
children from South Asia (McKinney et al., 2001).
It appears to be a clinically heterogeneous condition characterized by histological
variants (Border, 1988; Korbet,
1998; Myllymaki et al., 2003) and different
genetic backgrounds (Lenkkeri et al., 1999; Boute
et al., 2000; Kaplan et al., 2000)
with recessive and dominant inheritances. For these patients the therapeutic
option is a standard steroid therapy and on the basis of the patient's response
to steroid therapy, it is divided into Steroid-sensitive Nephrotic Syndrome
(SSNS) and Steroid-resistant Nephrotic Syndrome (SRNS) which may progress to
End-stage Renal Disease (ESRD) (Ruf et al., 2004).
It is the final result of various etiologies and prognostic indicators leading
to ESRD have been extensively studied, of which genetic factors remain a subject
of great concern (Uddin et al., 2007).
In INS the underlying histopathology can be Minimal Change Disease (MCD), Membranous
Nephropathy (MGN), Mesangioproliferative Nephropathy (MPGN) or Focal Segmental
Glomerulosclerosis (FSGS). MCD is milder with minimum abnormalities of the glomeruli
whereas FSGS is the most severe form causing collapse and scarring of some glomeruli
while others are intermediate forms (International Study
of Kidney Disease in Children, 1981). According to one report rate of apoptosis
is significantly higher in patients with FSGS (69%) compared to those with MCD
(Kamel et al., 2009). Explanation resides in
the fact that apoptosis is highly integrated in the pathogenesis of sclerotic
lesions. Schiffer et al., (2001) stated that
podocyte depletion leading to podocyte insufficiency and capillary collapse
have been invoked as important steps in the development of FSGS. High oxidative
stress associated with ACE activity has been suggested to lead to nephropathy
as the antioxidant defense systems are overloaded (Ghazi
et al., 2009).
ACE gene has 26 exons and spans 21 kb on chromosome 17q23 (Mattei
et al., 1989). The human ACE gene contains a number of variable polymorphic
regions that can be of potential use in genetic analysis of populations (Reider
et al., 1999). The Insertion/ Deletion (I/D) polymorphism, rs1799752
(Gard, 2010), present in intron 16, in particular has
been extensively investigated (Howard et al., 1990).
I/D polymorphism consists of the presence (Insertion-I) or absence (Deletion-D)
of 287 bp Alu repeat element in intron 16 resulting in 3 genotypes viz, Insertion
homozygote (I/I), Insertion/Deletion heterozygote (I/D) and Deletion homozygote
(D/D). The ACE I/D polymorphism are associated with overall plasma ACE levels
(Rigat et al., 1990). Individuals homozygous for
the D allele are characterized by elevated plasma levels of ACE compared with
individuals homozygous for I allele. ACE is a key enzyme that converts inactive
angiotensin I into a vasoactive and aldosterone-stimulating peptide angiotensin
II. High angiotensin II levels make deleterious effects on renal haemodynamics,
induces the expression of various growth factors, secretion of extracellular
matrix, inflammatory events that play a key role in glomerulosclerosis leading
to progression of renal diseases (Egido, 1996). The
objective of the current study was to investigate the role of ACE I/D gene polymorphism
on the susceptibility, progression and steroid response in INS from South Indian
MATERIALS AND METHODS
For the present study, blood samples were collected from a total of 418 subjects, 218 (146 males and 72 females) were clinically proven cases of INS fulfilling criteria of the International Study of Kidney Disease in Children for the diagnosis of INS without any secondary reasons for renal problem visiting Nephrology Department, NIMS hospital, Hyderabad, India and 200 were healthy volunteers of South Indian origin without any family history of renal disorders and preferred from the higher age group in order to rule out possibility of developing renal problems. Informed consent was obtained from all the participating subjects prior to blood sample collection. This study was approved by the Ethical committee at Osmania University. The mean age of the patient group was 15±11 years whereas for the control group it was 32±9 years. Blood samples as well as clinical data were collected in a well designed proforma from all the patients and controls for analysis.
Histopathological analysis was done based on biopsy findings for all the 218 patients. The follow up clinical data to evaluate steroid responsiveness was obtainable from 180 cases. Based on the underlying histopathology MCD could be termed as mild and MPGN+FSGS as severe. Steroid Sensitivity (SS) was defined as cessation of proteinuria for at least three consecutive days after standard steroid treatment. Steroid Dependence (SD) was defined as two consecutive relapses occurring during the period of steroid tapering or within 14 days of its cessation. No achievement of remission even after four weeks of steroid treatment was classified as Steroid Resistance (SR). SD and SR were grouped as Non-steroid sensitive (Non-SS).
Genomic DNA was extracted from all the 418 subjects in our laboratory using
standard salting out method (Miller et al., 1988).
ACE I/D genotyping was performed as given elsewhere (Surekha
et al., 2011) and to avoid mistyping of ID genotype as DD, 5% DMSO
was utilized. (Shanmugam et al.,1993). The gel
was analyzed on a gel documentation unit (Bio-Rad), PCR product of 490 bp indicate
homozygous for Insertion (II), 190 bp indicates homozygous for Deletion (DD)
and presence of both 490 and 190 bp indicate heterozygosity (ID) (Fig.
Comparisons of the data among different categories were performed by Chi-square test, Odds ratio and Z test with a 95% confidence interval. The p-value <0.05 was considered significant. Hardy-Weinberg equilibrium was evaluated by χ2 test for allelic frequency in patient and control group.
|| Agarose gel illustrating homozygous DD, homozygous II and
heterozygous ID genotype
The total study population comprised of 418 individuals, 218 INS patients and 200 controls. Male to female sex ratio of patients was 2:1 and the mean age was 15±11 years. The distribution of II, ID and DD genotypes in patients (n = 218) was 20.2, 42.2 and 37.6%, whereas, in the controls (n = 200), 43, 39.5 and 17.5%, respectively (Table 1). DD genotype was predominant in INS group (p = 0.0001). An odds ratio of 2.84 was obtained for DD vs. ID+II at 95% confidence interval.
Analysis of ACE I/D genotypes in different histopathological conditions of INS revealed 13, 33.33, 53.6 and 28.2, 48.3, 23% of II, ID and DD genotypes in severe and mild forms, respectively. An odds ratio of 3.76 was obtained for DD vs. ID+II at 95% confidence interval with p = 0.0001. Further D allele frequency was high in severe form than in mild form (0.7 vs. 0.47, OR = 2.67, p = 0.001) (Table 2). However, it did not deviate from Hardy Weinberg Equilibrium.
Distribution of ACE I/D genotypes II, ID and DD in SS and Non-SS groups was observed to be 18.4, 15.8, 67.5 and 17.3, 40.4, 42.3% correspondingly. With respect to steroid responsiveness DD homozygote behaved differently from that of ID heterozygote (DD vs. others: OR = 2.26, p = 0.002; ID vs. others: OR = 0.27, p = 0.0006). Elevated frequency of D allele (0.74 vs. 0.625) was observed in SS group compared to Non-SS group, however, did not reach to significance (p = 0.085) (Table 3).
|| Distribution of genotypes in patients and controls
|| Distribution of ACE I/D genotypes among mild and severe forms
|| Distribution of ACE I/D genotypes among steroid sensitive
and non-steroid sensitive patients
The ACE DD genotype is associated with the largest amount of angiotensin converting
enzyme and angiotensin II which has hemodynamic, growth and prosclerotic effects
(Yoshida et al., 1996). It is suggested that,
DD genotype acts as a predictor of progressive glomerulosclerosis in diabetic
nephropathy (Doria et al., 1994; Schmidt
et al., 1995a; Jeffers et al., 1997),
IgA nephropathy (Schmidt et al., 1995b; Yoshida
et al., 1995; Syrjanen et al., 2000)
and other chronic renal diseases (Yoshida et al.,
1996; Dudley et al., 2000; Hohenfeller
et al., 2001; Konoshita et al., 2001).
The present study on ACE I/D gene polymorphism provides clues for understanding
the susceptibility, clinical status and the benefit of steroid therapy in INS
ACE I/D gene polymorphisms in the susceptibility to INS: The current
study dealt with distribution of ACE I/D gene polymorphism in INS and normal
individuals of South Indian population. Analysis showed that DD vs. ID+II comparison
among the two groups were significantly different (p = 0.0001) and clearly ascertain
that DD genotype is a high risk genotype as the OR value was found to be as
high as 2.84 (95% CI p = 0.0001). DD genotype with double dose of D allele almost
have five fold increased risk of developing INS (DD vs. II, OR = 4.58, p<0.0001)
compared to II homozygotes which has no D allele. The genotype ID with a single
dose of D allele exhibited more than two fold increased risk compared to II
(ID vs. II, OR = 2.27 p = 0.0006). This shows a graded risk of DD>ID genotypes
to INS which may be correlated with the ace levels and suggest that D allele
can be an independent marker of susceptibility to nephrotic syndrome in south
Indian population. Studies suggest the association of DD genotype not only in
secondary renal abnormalities (Doria et al., 1994;
Schmidt et al., 1995a; Jeffers
et al., 1997; Uddin et al., 2007)
but also in primary nephropathy (Lee et al., 1997;
Serdaroglu et al., 2005; Tsai
et al., 2006). A meta analysis concluded that II subjects had a 22%
lower risk of diabetic nephropathy than the D allele carriers and Asians derived
greater protection than Caucasians (Ng et al., 2009).
ACE I/D gene polymorphisms in relation to severity of INS: When patients
were categorized on the basis of histopathology (methodology section) and analyzed
for the distribution of ACE I/D genotypes, II homozygotes were significantly
predominant in the mild form and DD homozygotes in the severe form. This is
in accordance to the earlier reports from Japan and Korea (Lee
et al., 1997; Hori et al., 2001).
It was stated that, intrarenal concentration of angiotensin II in the individuals
with ACE DD genotype was 1,000 times more than that of the concentration in
plasma which may increase the intraglomerular pressure, induces transforming
growth factor (TGF-β) to exert a prosclerotic activity leading to glomerular
sclerosis (Wolf et al., 1993; Egido,
1996; El-Mesallamy et al., 2008), thus a
cause for progression of MCD to FSGS in DD homozygotes. Elevated levels of IFN-γ
as a consequence of TGF-β signalling have been reported to cause diabetic
nephropathy (Nosratabadi et al., 2009).
ACE I/D gene polymorphisms and steroid responsiveness of INS patients:
When steroid sensitivity was correlated with ACE I/D polymorphism it was observed
that ID individuals are 3 times more resistant to steroids compared to other
genotypes (z = 3.45, p = 0.0006), whereas, DD individuals are almost two times
more sensitive to steroids (z = 2.26, p = 0.0021). II homozygotes were represented
equally in both the groups indicating II homozygous condition does not influence
steroid responsiveness, thus providing an appropriate example to cite how differently
homozygotes and heterozygotes behave. The involvement of ID genotype with steroid
resistance may be due to unexplained allelic interactions among I and D allele.
Similar results were obtained by a Turkish study (Celik
et al., 2006). An investigation by Fahmy et
al. (2008) in Egyptian children has reported prevalence of II individuals
in the steroid sensitive group and DD individuals in steroid non-sensitive group
and no difference with respect to ID frequency in cases and controls contrary
to our results; however, their sample size was smaller compared to the present
study and also belonged to a different ethnic group. In addition, one study
from North India by Patil et al. (2005) has reported
a significantly higher incidence of II genotype than the controls but their
study is restricted to steroid sensitive patients and recommended studies comparing
genotype frequency with steroid resistant patients for understanding the influence
of ACE genotypes in steroid responsiveness. Understanding the mechanism of action
of steroids in reducing the proteinuria may throw light on response to steroids
and ACE inhibitors in nephrotic syndrome (Vegter et al.,
In conclusion ACE I/D genotypes do significantly influence the susceptibility, progression and drug response variation in INS of South Indian population. This information may help the clinicians to predict the course of disease and to identify individuals with better prognosis to standard steroid treatment. Not many studies are cited in literature on the role of ACE I/D genotypes and steroid responsiveness but the ones that are available have limited sample size. However, the present study dealt with comparison of SSNS and SRNS groups to understand the genotypic distribution or the ACE I/D allele involvement. In order to delineate the role of different genotypes on the above aspects, its influence at the physiological level has to be studied with large sample size in different ethnic groups.
Border, W.A., 1988.
Distinguishing minimal-change disease from mesangial disorders. Kidney Int., 34: 419-434.CrossRef | Direct Link |
Boute, N., O. Gribouval, S. Roselli, F. Benessy and H. Lee et al
NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat. Genet., 24: 349-354.CrossRef | PubMed |
Braden, G.L., J.G. Mulhern, M.H. O`Shea, S.V. Nash, A.A. Ucci Jr. and M.J. Germain, 2000.
Changing incidence of glomerular diseases in adults. Am. J. Kidney Dis., 35: 878-883.PubMed | Direct Link |
Celik, U.S., A. Noyan, A.K. Bayazit, M. Buyukcelik and H. Dursun et al
ACE gene polymorphism in Turkish children with nephrotic syndrome. Renal Fail., 28: 401-403.CrossRef | PubMed | Direct Link |
Doria, A., J. Warram and A. Krolewski, 1994.
Genetic predisposition to diabetic nephropathy. Evidence for a role of the angiotensin I-converting enzyme gene. Diabetes, 43: 690-695.PubMed | Direct Link |
Dudley, J., E. Afifi, A. Gardner, E.J. Tizard and M.E. McGraw, 2000.
Polymorphism of the ACE gene in Henoch-Schonlein purpura nephritis. Pediatric Nephrol., 14: 218-220.CrossRef | PubMed | Direct Link |
Al-Omireeni, E.A., N.J. Siddiqi and A.S. Alhomida, 2011.
Effect of different doses of sodium fluoride on various hydroxyproline fractions in rat kidneys. Kidney Res. J., 1: 33-40.CrossRef | Direct Link |
Egido, J., 1996.
Vasoactive hormones and renal sclerosis. Kidney Int., 49: 578-597.CrossRef | Direct Link |
Ghazi, F., M. Firoozrai, B. Dabirmanesh and A. Shabani, 2009.
Serum angiotensin converting enzyme activity total antioxidants and ascorbic acid in iranian patients with coronary artery disease. J. Biol. Sci., 9: 612-616.CrossRef |
Mortazavi, F. and A. Rafiee, 2010.
Etiology of pediatric chronic kidney diseases in North-West of Iran. Pak. J. Biol. Sci., 13: 456-459.CrossRef | Direct Link |
Fahmy, M.E., A.M. Fattouh, R.A. Hegazy and M.L. Essawi, 2008.
ACE gene polymorphism in Egyptian children with idiopathic nephrotic syndrome. Brastisl Lek Listy, 109: 298-301.PubMed | Direct Link |
El-Mesallamy, H.O., R.S. Salah and M.Z. Gad, 2008.
Study of some inflammatory factors in type 2 diabetic patients with nephropathy. J. Med. Sci., 8: 532-539.CrossRef | Direct Link |
Hohenfeller, K., A.M. Wingren, O. Nauroth, E. Wuhl, O. Mehls and F. Schaefer, 2001.
Impact of ACE I/D gene polymorphism on congenital renal malformations. Pediatric Nephrol., 16: 356-361.CrossRef | PubMed | Direct Link |
Hori, C., M. Hiraoka, N. Yoshikawa, K. Tsuzuki and Y. Yoshida et al
Significance of ACE genotypes and medical treatments in childhood focal glomerulosclerosis. Nephron, 88: 313-319.CrossRef | PubMed | Direct Link |
Howard, T.E., S.Y. Shai, K.G. Langford, B.M. Martin and K.E. Bernstein, 1990.
Transcription of testicular Angiotensin-Converting Enzyme (ACE) is initiated within the 12th intron of the somatic ACE gene. Mol. Cell. Biol., 10: 4294-4302.PubMed | Direct Link |
Yoshida, H., V. Kon and I. Ichikawa, 1996.
Polymorphisms of the renin-angiotensin system genes in progressive renal diseases. Kidney Int., 50: 732-744.CrossRef | Direct Link |
International Study of Kidney Disease in Children, 1981.
The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the international study of kidney disease in children. J. Pediatrics, 98: 561-564.PubMed | Direct Link |
Jeffers, B.W., R.O. Estacio, M.V. Raynolds and R.W. Schrier, 1997.
Angiotensin-converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus and its relationship with diabetic nephropathy. Kidney Int., 52: 473-477.CrossRef | Direct Link |
Kaplan, J.M., S.H. Kim, K.N. North, H. Rennke and L.A. Correia et al
Mutations in ACTN4
, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis. Nat. Genet., 24: 251-256.CrossRef | PubMed | Direct Link |
Konoshita, T., K. Miyagi, T. Onoe, K. Katano and H. Mutoh et al
Effect of ACE gene polymorphism on age at renal death in polycystic kidney disease in Japan. Am. J. Kidney Dis., 37: 113-118.CrossRef | Direct Link |
Korbet, S.M., 1998.
Primary focal segmental glomerulosclerosis. J. Am. Soc. Nephrol., 9: 1333-1340.PubMed | Direct Link |
Lee, D.Y., W. Kim, S.K. Kang, G.Y. Koh and S.K. Park, 1997.
Angiotensin-converting enzyme gene polymorphism in patients with minimal-change nephrotic syndrome and focal segmental glomerulosclerosis. Nephron, 77: 471-473.PubMed | Direct Link |
Lenkkeri, U., M. Mannikko, P. McCready, J. Lamerdin and O. Gribouval et al
Structure of the gene for congenital nephrotic syndrome of the finnish type (NPHS1) and characterization of mutations. Am. J. Hum. Genet., 64: 51-61.CrossRef | PubMed | Direct Link |
Mattei, M.G., C. Hubert, F. Alhenc-Gelas, N. Roeckel, P. Corvol and F. Soubrier, 1989.
Angiotensin-I converting enzyme gene is on chromosome 17. Cytogenet. Cell. Genet., 51: 1041-1045.
McKinney, P.A., R.G. Feltbower, J.T. Brocklebank and M.M. Fitzpatrick, 2001.
Time trends and ethnic patterns of childhood nephrotic syndrome in Yorkshire, UK. Pediatric Nephrol., 16: 1040-1044.CrossRef | PubMed | Direct Link |
Uddin, M., M. Azam, N. Chowdhury and S. Akhteruzzaman, 2007.
Angiotensin I-converting enzyme gene polymorphism intype 2 diabetic patients with nephropathy. J. Med. Sci., 7: 682-685.CrossRef | Direct Link |
Miller, S.A., D.D. Dykes and H.F. Polesky, 1988.
A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res., 16: 1215-1215.PubMed | Direct Link |
Myllymaki, J., H. Saha, J. Mustonen, H. Helin and A. Pasternack, 2003.
IgM nephropathy: Clinical picture and long-term prognosis. Am. J. Kidney Dis., 41: 343-350.CrossRef | PubMed | Direct Link |
Ng, D., S.N.B. Ramli, K.S. Chia, D. Koh and B.C. Tai, 2009.
Genetic variation at the angiotensin-I converting enzyme locus and the risk for diabetic nephropathy: A study based on 53 studies and 17 791 subjects. Salud I Ciencia, 16: 751-754.
Patil, S.J., S. Gulati, F. Khan, M. Tripathi, M. Ahmed and S. Agrawal, 2005.
Angiotensin converting enzyme gene polymorphism in Indian children with steroid sensitive nephrotic syndrome. Indian J. Med. Sci., 59: 431-435.CrossRef | PubMed | Direct Link |
Gard, P.R., 2010.
Implications of the angiotensin converting enzyme gene insertion/deletion polymorphism in health and disease: A snapshot review. Int. J. Mol. Epidemiol. Genet., 1: 145-157.PubMed | Direct Link |
Ruf, R.G., A. Lichtenberger, S.M. Karle, J.P. Haas and F.E. Anacleto et al
Patients with mutations in NPHS2 (Podocin) do not respond to standard steroid treatment of nephrotic syndrome. J. Am. Soc. Nephrol., 15: 722-732.CrossRef | PubMed | Direct Link |
Reider, M.J., S.L. Taylor, A.G. Clark and D.A. Nickerson, 1999.
Sequence variation in the human angiotensin converting enzyme. Nat. Genet., 22: 59-62.CrossRef | PubMed | Direct Link |
Nosratabadi, R., M.K. Arababadi, G. Hassanshahi, N. Yaghini and V. Pooladvand et al
Evaluation of IFN-γ serum level in nephropatic type 2 diabetic patients. Pak. J. Biol. Sci., 12: 746-749.CrossRef | PubMed | Direct Link |
Rigat, B., C. Hubert, F. Alhenc-Gelas, F. Cambien, P. Corvol and F. Soubrier, 1990.
An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J. Clin. Invest., 86: 1343-1346.CrossRef | PubMed | Direct Link |
Saber, K., Z. El-Khayat, G.S. Hussein and A.N. Hanna, 2007.
Study of tissue factor and factor Vila in children with nephrotic syndrome. J. Med. Sci., 7: 111-115.CrossRef | Direct Link |
Schiffer, M., M. Bitzer and I.S. Roberts, 2001.
Apoptosis in podocytes induced by TGF-beta and Smad 7. Clin. Invest., 108: 807-816.PubMed |
Schmidt, S., N. Schone and E. Ritz, 1995.
The diabetic nephropathy study group. Association of ACE gene polymorphism and diabetic nephropathy? Kidney Int., 47: 1176-1181.
Schmidt, S., E. Stier, R. Hartung, G. Stein and J. Bahnisch et al
No association of converting enzyme insertion/deletion polymorphism with immunoglobulin A glomerulonephritis. Am. J. Kidney Dis., 26: 727-731.PubMed | Direct Link |
Serdaroglu, E., S. Mir, A. Berdeli, N. Aksu and M. Bak, 2005.
ACE gene insertion/deletion polymorphism in childhood idiopathic nephrotic syndrome. Pediatric Nephrol., 20: 1738-1743.CrossRef | PubMed | Direct Link |
Syrjanen, J., X. Huang, J. Mustonen, T. Koivula, T. Lehtimaki and A. Pasternack, 2000.
Angiotensin-converting enzyme insertion/deletion polymorphism and prognosis of IgA nephropathy. Nephron, 86: 115-121.CrossRef | PubMed | Direct Link |
Surekha, T., M. Ishaq, K. Prasanna and P. Jahan, 2011.
Angiotensin Converting Enzyme (ACE) gene polymorphism in vitiligo: Protective and predisposing effects of genotypes in disease susceptibility and progression. Eur. J. Dermatol., 21: 173-177.PubMed | Direct Link |
Tsai, I.J., Y.H. Yang, Y.H. Lin, V.C. Wu, Y.K. Tsau and F.J. Hsieh, 2006.
Angiotensin-converting enzyme gene polymorphism in children with idiopathic nephrotic syndrome. Am. J. Nephrol., 26: 157-162.CrossRef | Direct Link |
Shanmugam, V., K.W. Sell and B.K. Saha, 1993.
Mistyping ACE heterozygotes. Genome Res., 3: 120-121.CrossRef | Direct Link |
Vegter, S., A. Perna, W. Hiddema, P. Ruggenenti, G. Remuzzi, G. Navis and M.J. Postma, 2009.
Cost-effectiveness of ACE inhibitor therapy to prevent dialysis in nondiabetic nephropathy: Influence of the ACE insertion/deletion polymorphism. Pharmacogenet. Genomics, 19: 695-703.CrossRef | PubMed | Direct Link |
Wolf, G., E. Mueller, R.A.K. Stahl and F.N. Zyadeh, 1993.
Angiotensin II-induced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factor-β. J. Clin. Invest., 92: 1366-1372.CrossRef | Direct Link |
Kamel, Y.H., H.M. Bazaraa, A.E. Elwan, N.A. Fahmy and O. Shaker, 2009.
Apoptotic markers in childhood nephrotic syndrome. J. Biol. Sci., 9: 509-513.CrossRef | Direct Link |
Yoshida, H., T. Mitarai, T. Kawamura, T. Kitajima and Y. Miyazaki et al
Role of the deletion of polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy. J. Clin. Invest., 96: 2162-2169.CrossRef | PubMed | Direct Link |