Abstract
The phosphodiesterase-5 (PDE-5) gene is highly specific to cyclic GMP (cGMP) and several experimental studies have shown that the nitric oxide/cGMP pathway plays an important role in the pathogenesis of glomerulonephritis, including IgA nephropathy (IgAN). The present study was conducted to investigate the association among 16 single nucleotide polymorphisms (SNPs) of PDE5A and childhood IgAN. The genotyping data from 160 patients with childhood IgAN and 454 controls showed a significant difference in rs13124532 (codominant, P = 0.005; dominant, P = 0.005). Furthermore, patient subgroup analysis revealed an association between the development of proteinuria (>4 and ≤4 mg/m2/h) and rs13124532 (codominant, P = 0.008; dominant, P = 0.011), and between the nephrotic range proteinuria (> 40 mg/m2/h) and rs11734241 (dominant, P = 0.035), rs12510138 (dominant, P = 0.028), rs13134665 (dominant, P = 0.025), rs3822192 (dominant, P = 0.027), rs10013305 (dominant, P = 0.020), rs1480940 (dominant, P = 0.020), rs1480936 (dominant, P = 0.019), rs11947234 (dominant, P = 0.019), and rs2127823 (dominant, P = 0.026). The pathological findings showed that rs13124532 had an association with podocyte foot process effacement (codominant, P = 0.035; dominant, P = 0.044) and with pathological progression (codominant, P = 0.046). Our results suggest that PDE5A is associated with increased disease susceptibility, pathological progression, and development of proteinuria in childhood IgAN.
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Abbreviations
- GN:
-
Glomerulonephritis
- IgAN:
-
IgA nephropathy
- LD:
-
Linkage disequilibrium
- PDE5A :
-
Phosphodiesterase 5A
- SNP:
-
Single nucleotide polymorphism
References
Fogo AB (2007) Mechanisms of progression of chronic kidney disease. Pediatr Nephrol 22:2011–2022
Barratt J, Smith AC, Molyneux K, Feehally J (2007) Immunopathogenesis of IgAN. Semin Immunopathol 29:427–443
Hohenstein B, Daniel C, Wittmann S, Hugo C (2008) PDE-5 inhibition impedes TSP-1 expression, TGF-beta activation and matrix accumulation in experimental glomerulonephritis. Nephrol Dial Transplant 23:3427–3436
Kotera J, Fujishige K, Omori K (2000) Immunohistochemical localization of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in rat tissues. J Histochem Cytochem 48:685–693
Knight S, Snellen H, Humphreys M, Baylis C (2007) Increased renal phosphodiesterase-5 activity mediates the blunted natriuretic response to ANP in the pregnant rat. Am J Physiol Renal Physiol 292:F655–F659
Rodriguez-Iturbe B, Ferrebuz A, Vanegas V, Quiroz Y, Espinoza F, Pons H, Vaziri ND (2005) Early treatment with cGMP phosphodiesterase inhibitor ameliorates progression of renal damage. Kidney Int 68:2131–2142
Lee KW, Jeong JY, Lim BJ, Chang YK, Lee SJ, Na KR, Shin YT, Choi DE (2009) Sildenafil attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity. Toxicology 257:137–143
Hosogai N, Tomita M, Hamada K, Ogawa T, Hirosumi J, Manda T, Mutoh S (2003) Phosphodiesterase type 5 inhibition ameliorates nephrotoxicity induced by cyclosporin A in spontaneous hypertensive rats. Eur J Pharmacol 477:171–178
Furusu A, Miyazaki M, Abe K, Tsukasaki S, Shioshita K, Sasaki O, Miyazaki K, Ozono Y, Koji T, Harada T, Sakai H, Kohno S (1998) Expression of endothelial and inducible nitric oxide synthase in human glomerulonephritis. Kidney Int 53:1760–1768
Kashem A, Endoh M, Yano N, Yamauchi F, Nomoto Y, Sakai H (1996) Expression of inducible-NOS in human glomerulonephritis: the possible source is infiltrating monocytes/macrophages. Kidney Int 50:392–399
Qiu LQ, Sinniah R, Hsu SI (2004) Coupled induction of iNOS and p53 upregulation in renal resident cells may be linked with apoptotic activity in the pathogenesis of progressive IgA nephropathy. J Am Soc Nephrol 15:2066–2078
Merta M, Reiterova J, Tesar V, Stekrova J, Viklicky O (2002) Influence of the endothelial nitric oxide synthase polymorphism on the progression of autosomal dominant polycystic kidney disease and IgA nephropathy. Ren Fail 24:585–593
Morita T, Ito H, Suehiro T, Tahara K, Matsumori A, Chikazawa H, Nakauchi Y, Nishiya K, Hashimoto K (1999) Effect of a polymorphism of endothelial nitric oxide synthase gene in Japanese patients with IgA nephropathy. Clin Nephrol 52:203–209
Burg M, Menne J, Ostendorf T, Kliem V, Floege J (1997) Gene-polymorphisms of angiotensin converting enzyme and endothelial nitric oxide synthase in patients with primary glomerulonephritis. Clin Nephrol 48:205–211
Hong Q, Ding R, Chen XM, Lu Y (2006) Association between endothelial nitric oxide synthase gene 4a/b polymorphism and IgA nephropathy. Nan Fang Yi Ke Da Xue Xue Bao 26(1421–1422):1430
Alasehirli B, Balat A, Barlas O, Kont A (2009) Nitric oxide synthase gene polymorphisms in children with minimal change nephrotic syndrome. Pediatr Int 51:75–78
Kim W, Kang SK, Lee DY, Koh GY, Lee KY, Park SK (2000) Endothelial nitric oxide synthase gene polymorphism in patients with IgA nephropathy. Nephron 86:232–233
Lim SC, Liu JJ, Low HQ, Morgenthaler NG, Li Y, Yeoh LY, Wu YS, Goh SK, Chionh CY, Tan SH, Kon YC, Soon PC, Bee YM, Subramaniam T, Sum CF, Chia KS (2009) Microarray analysis of multiple candidate genes and associated plasma proteins for nephropathy secondary to type 2 diabetes among Chinese individuals. Diabetologia 52:1343–1351
Rodriguez-Perez JC, Macias-Reyes A, Jimenez-Sosa A, Companioni O, Rodriguez-Esparragon FJ, Cobo MA, Checa-Andres MD, Palop-Cubillo L, Alonso A, Torres A (2009) A synergistic association of ACE I/D and eNOS G894T gene variants with the progression of immunoglobulin a nephropathy—a pilot study. Am J Nephrol 30:303–309
Salvi F, Sarzani R, Giorgi R, Donatelli G, Pietrucci F, Micheli A, Baldoni M, Minardi D, Dessi-Fulgheri P, Polito M, Muzzonigro G, Rappelli A (2004) Cardiovascular effects of sildenafil in hypertensive men with erectile dysfunction and different alleles of the type 5 cGMP-specific phosphodiesterase (PDE5). Int J Impot Res 16:412–417
Lee HS, Lee MS, Lee SM, Lee SY, Lee ES, Lee EY, Park SY, Han JS, Kim S, Lee JS (2005) Histological grading of IgA nephropathy predicting renal outcome: revisiting H.S. Lee’s glomerular grading system. Nephrol Dial Transplant 20:342–348
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229
Zhu Y, Yao J, Meng Y, Kasai A, Hiramatsu N, Hayakawa K, Miida T, Takeda M, Okada M, Kitamura M (2006) Profiling of functional phosphodiesterase in mesangial cells using a CRE-SEAP-based reporting system. Br J Pharmacol 148:833–844
Choi DE, Jeong JY, Lim BJ, Chung S, Chang YK, Lee SJ, Na KR, Kim SY, Shin YT, Lee KW (2009) Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats. Am J Physiol Renal Physiol 297:F362–370
Lau DH, Mikhailidis DP, Thompson CS (2007) The effect of vardenafil (a PDE type 5 inhibitor) on renal function in the diabetic rabbit: a pilot study. In Vivo 21:851–854
Chiu YJ, Reid IA (2002) Effect of sildenafil on renin secretion in human subjects. Exp Biol Med (Maywood) 227:620–625
Thiesson HC, Jensen BL, Jespersen B, Schaffalitzky de Muckadell OB, Bistrup C, Walter S, Ottosen PD, Veje A, Skott O (2005) Inhibition of cGMP-specific phosphodiesterase type 5 reduces sodium excretion and arterial blood pressure in patients with NaCl retention and ascites. Am J Physiol Renal Physiol 288:F1044–F1052
Conne B, Stutz A, Vassalli JD (2000) The 3′ untranslated region of messenger RNA: a molecular ‘hotspot’ for pathology? Nat Med 6:637–641
Hughes TA (2006) Regulation of gene expression by alternative untranslated regions. Trends Genet 22:119–122
Olsen PH, Ambros V (1999) The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. Dev Biol 216:671–680
Komar AA (2007) Silent SNPs: impact on gene function and phenotype. Pharmacogenomics 8:1075–1080
Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM (2007) A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–528
Ying SY, Chang CP, Lin SL (2010) Intron-mediated RNA interference, intronic microRNAs, and applications. Methods Mol Biol 629:205–237
Malisic EJ, Jankovic RN, Radulovic SS (2010) An intronic variant in the TP53 gene in Serbian women with cervical or ovarian cancer. Cancer Genet Cytogenet 198:173–175
Maruyama K, Yoshida M, Nishio H, Shirakawa T, Kawamura T, Tanaka R, Nakamura H, Iijima K, Yoshikawa N (2001) Polymorphisms of renin-angiotensin system genes in childhood IgA nephropathy. Pediatr Nephrol 16:350–355
Nakanishi K, Sako M, Yata N, Aoyagi N, Nozu K, Tanaka R, Iijima K, Yoshikawa N (2004) A-20C angiotensinogen gene polymorphism and proteinuria in childhood IgA nephropathy. Pediatr Nephrol 19:144–147
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This research was supported by the Program of Kyung Hee University for the Young Researcher of Medical Science in 2009 (KHU-20091437).
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Hahn, WH., Suh, JS. & Cho, BS. Phosphodiesterase-5 gene (PDE5A) polymorphisms are associated with progression of childhood IgA nephropathy. Pediatr Nephrol 25, 1663–1671 (2010). https://doi.org/10.1007/s00467-010-1579-x
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DOI: https://doi.org/10.1007/s00467-010-1579-x