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 firstname.lastname@example.org.
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
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