Am J Physiol Renal Physiol. 2016 Mar 1;310(5):F416-25.
Aquaporin 11 variant associates with kidney disease in type 2 diabetic patients.
- 1Division of Nephrology and Hypertension, Vanderbilt University, Nashville, Tennessee;
- 2Knowledge Management/Research Informatics Consult Service, Vanderbilt University, Nashville, Tennessee;
- 3Kentucky College of Osteopathic Medicine, University of Pikeville, Pikeville, Kentucky;
- 4Mathematics Department, University of Missouri, Columbia, Missouri;
- 5University of Illinois, Champaign, Illinois;
- 6Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio.
- 7Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio email@example.com.
Kidney disease, a common complication of diabetes, associates with poor prognosis. Our previous animal model studies linked aquaporin (AQP)11 to acute kidney injury, hyperglycemia-induced renal impairment, and kidney disease in diabetes. Here, we report the AQP11 rs2276415 variant as a genetic factor placing type 2 diabetic patients at greater risk for the development of kidney disease. We performed two independent retrospective case-control studies in 1,075 diabetic and 1,619 nondiabetic individuals who were identified in the Synthetic Derivative Database with DNA samples in the BioVU DNA repository at Vanderbilt University (Nashville, TN). A χ(2)-test and multivariable logistic regression analysis with adjustments for age, sex, baseline serum creatinine, and underlying comorbid disease covariates showed a significant association between rs2276415 and the prevalence of any event of acute kidney injury and chronic kidney disease (CKD) in diabetic patients but not in patients without diabetes. This result was replicated in the second independent study. Diabetic CKD patients over 55 yrs old with the minor AQP11 allele had a significantly faster progression of estimated glomerular filtration rate decline than patients with the wild-type genotype. Three-dimensional structural analysis suggested a functional impairment of AQP11 with rs2276415, which could place diabetic patients at a higher risk for kidney disease. These studies identified rs2276415 as a candidate genetic factor predisposing patients with type 2 diabetes to CKD.
KEYWORDS: acute kidney injury; chronic kidney injury; diabetes mellitus; proximal tubules
Single nucleotide polymorphism (SNP), a common type of genetic variation in humans, often results in amino acid substitution in functional structure of the protein encoded by the gene. Such SNP, as a genetic risk factor, might modulate the protein function predisposing a host to disease due to acute or chronic stress.
Epidemiologic studies clearly indicate a genetic basis for the risk of chronic kidney disease (CKD), an irreversible fibrotic kidney complication of diabetes(4, 7, 17). The identity of the genetic risk factors that predispose diabetic patients to CKD has been the subject of many studies, including large-scale clinical genetic studies: Family Investigation of Nephropathy and Diabetes (FIND) and Genetics of Kidney in Diabetes (GoKinD)(6, 13). While genetic variants at different chromosomes have been linked to diabetic kidney disease in human patients, gene identification and causative connection between genetic modifiers and diabetic kidney disease remain uncertain(6, 8, 11, 13, 16).
For the first time we reported that genetic polymorphism of human aquaporin 11 (AQP11) gene causing Gly102Ser amino acid substitution in the AQP11 protein was associated with significantly higher risk of CKD in diabetic patients, thus implicating AQP11 in the onset of this complication. The AQP11, a recently discovered member of the transport protein superfamily, is exclusively expressed in proximal tubules (PT) in kidney(12, 18, 19). Proximal tubules are the important segments of nephron, a smallest functional unit of the kidney, and a major site of glucose and water flux in kidney. AQP11 is profoundly involved in PT physiology and resides in the endoplasmic reticulum (ER). It has a protective function against oxidative stress-induced insult by ameliorating ER stress(1), and is implicated in the maintenance of ER homeostasis in PT(12, 15),(5, 14, 21).
Our current investigation corroborates studies suggesting that PT might be a triggering site of irreversible fibrotic changes in kidney and progression of diabetic CKD(9). Our data clearly indicate the AQP11 SNP as a potential genetic risk factor that may reinforce fibrinogenesis in diabetic kidney. They significantly advance knowledge of novel genetic risk factors predisposing to diabetic CKD and might have enormous positive consequences for the identification of diabetic patients at risk of this disease and for the preventive therapies
Risk assessment using genetic testing for disease susceptibility is the first stage of personalized medicine approach to patient care. The NIH’s National Kidney Disease Education Program indicated that prevention is a way to reduce the human and economic costs of CKD and ESRD in diabetic patients (http://report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid=34). Thus, the implementation of our research to personalized medicine would include assay for the identification of AQP11 SNP in patients with diabetes. This will help to: 1) Identify diabetic patients predisposed to CKD; 2) Benefit care with the preventative therapies; and 3) Facilitate the development of novel therapeutic agents to preserve renal function in the diabetic patients.
Clarifying the role of AQP11 dysfunction in renal hyperglycemia-induced injury would have tremendous implications in our understanding of the primary causes and mechanisms of diabetic CKD and in facilitating the development of novel therapeutic agents to preserve renal function that will benefit high-risk diabetic patient care.
Elena E. Tchekneva, MD
Assistant Professor of Internal Medicine
The Ohio State University Medical Center
- Atochina-Vasserman E, Biktasova, A, Abramova, E, Cheng, D-S, Polosukhin,VV, Tanjore, H, Takahashi, S, Sonoda, H, Foye, L, Venkov, C, Ryzhov, SV, Novitskiy, S, Shlonimskaya, N, Ikeda, M, Blackwell, TS, Lawson, WE, Gow, AJ, Harris, RC, Dikov, MM, Tchekneva, EE. Aquaporin 11 Insufficiency Modulates Kidney Susceptibility to Oxidative Stress. American Journal of Physiology – Renal Physiology 304: F1295-F1307, 2013.
- Hannedouche TP, Delgado AG, Gnionsahe DA, Boitard C, Lacour B, and Grunfeld JP. Renal hemodynamics and segmental tubular reabsorption in early type 1 diabetes. Kidney Int 37: 1126-1133, 1990.
- Huang HC, and Preisig PA. G1 kinases and transforming growth factor-beta signaling are associated with a growth pattern switch in diabetes-induced renal growth. Kidney Int 58: 162-172, 2000.
- Imperatore G, Knowler WC, Nelson RG, and Hanson RL. Genetics of diabetic nephropathy in the Pima Indians. Curr Diab Rep 1: 275-281, 2001.
- Ishibashi K, Kobayashi, K ., Sohara, E., Sasaki, S., Saihara, Y. Aquaporin-11(AQP11) is important for cytosolic osmoregulation. J Am Soc Nephrol 17: 539A, 2006.
- Knowler WC, Coresh J, Elston RC, Freedman BI, Iyengar SK, Kimmel PL, Olson JM, Plaetke R, Sedor JR, and Seldin MF. The Family Investigation of Nephropathy and Diabetes (FIND): design and methods. J Diabetes Complications 19: 1-9, 2005.
- Krolewski AS, Canessa M, Warram JH, Laffel LM, Christlieb AR, Knowler WC, and Rand LI. Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N Engl J Med 318: 140-145, 1988.
- Kure M, Pezzolesi MG, Poznik GD, Katavetin P, Skupien J, Dunn JS, Mychaleckyj JC, Warram JH, and Krolewski AS. Genetic variation in the matrix metalloproteinase genes and diabetic nephropathy in type 1 diabetes. Mol Genet Metab 103: 60-65, 2011.
- Magri CJ, and Fava S. The role of tubular injury in diabetic nephropathy. Eur J Intern Med 20: 551-555, 2009.
- Mbanya JC, Thomas TH, Taylor R, Alberti KG, and Wilkinson R. Increased proximal tubular sodium reabsorption in hypertensive patients with type 2 diabetes. Diabet Med 6: 614-620, 1989.
- Mooyaart AL, Valk EJ, van Es LA, Bruijn JA, de Heer E, Freedman BI, Dekkers OM, and Baelde HJ. Genetic associations in diabetic nephropathy: a meta-analysis. Diabetologia 54: 544-553, 2011.
- Morishita Y, Matsuzaki T, Hara-chikuma M, Andoo A, Shimono M, Matsuki A, Kobayashi K, Ikeda M, Yamamoto T, Verkman A, Kusano E, Ookawara S, Takata K, Sasaki S, and Ishibashi K. Disruption of aquaporin-11 produces polycystic kidneys following vacuolization of the proximal tubule. Mol Cell Biol 25: 7770-7779, 2005.
- Mueller PW, Rogus JJ, Cleary PA, Zhao Y, Smiles AM, Steffes MW, Bucksa J, Gibson TB, Cordovado SK, Krolewski AS, Nierras CR, and Warram JH. Genetics of Kidneys in Diabetes (GoKinD) study: a genetics collection available for identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes. J Am Soc Nephrol 17: 1782-1790, 2006.
- Nozaki K, Ishii D, and Ishibashi K. Intracellular aquaporins: clues for intracellular water transport? Pflugers Arch 456: 701-707, 2008.
- Okada S, Misaka T, Tanaka Y, Matsumoto I, Ishibashi K, Sasaki S, and Abe K. Aquaporin-11 knockout mice and polycystic kidney disease animals share a common mechanism of cyst formation. Faseb J 22: 3672-3684, 2008.
- Puppala S, Arya R, Thameem F, Arar NH, Bhandari K, Lehman DM, Schneider J, Fowler S, Farook VS, Diego VP, Almasy L, Blangero J, Stern MP, Duggirala R, and Abboud HE. Genotype by diabetes interaction effects on the detection of linkage of glomerular filtration rate to a region on chromosome 2q in Mexican Americans. Diabetes 56: 2818-2828, 2007.
- Seaquist ER, Goetz FC, Rich S, and Barbosa J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320: 1161-1165, 1989.
- Tchekneva EE, Khuchua Z, Davis LS, Kadkina V, Dunn SR, Bachman S, Ishibashi K, Rinchik EM, Harris RC, Dikov MM, and Breyer MD. Single amino acid substitution in aquaporin 11 causes renal failure. J Am Soc Nephrol 19: 1955-1964, 2008.
- Tchekneva EE, Rinchik, E.M., Dunn, S.R., Bachman, S., Polosukhina, D., Kadkina, V., Breyer, M.D. . Proximal tubule injury and sudden juvenile death syndrome (sjds) in mutant mice carrying a recessive ENU-induced mutation on chromosome 7. . J Am Soc Neph 16: 141A, 2005.
- Vallon V, Blantz R, and Thomson S. The salt paradox and its possible implications in managing hypertensive diabetic patients. Curr Hypertens Rep 7: 141-147, 2005.
- Yakata K, Tani K, and Fujiyoshi Y. Water permeability and characterization of aquaporin-11. J Struct Biol 174: 315-320, 2011.
- Zerbini G, Bonfanti R, Meschi F, Bognetti E, Paesano PL, Gianolli L, Querques M, Maestroni A, Calori G, Del Maschio A, Fazio F, Luzi L, and Chiumello G. Persistent renal hypertrophy and faster decline of glomerular filtration rate precede the development of microalbuminuria in type 1 diabetes. Diabetes 55: 2620-2625, 2006.