Diabetic nephropathy (DN) is a major source of morbidity and mortality. Both the incidence and prevalence of ESRD secondary to diabetes continue to rise. In the United States, over 30% of patients receiving either dialysis therapy or renal transplantation have ESRD as a result of diabetic nephropathy, and more than 40% of the incident cases of ESRD are attributable to diabetes. Given the global epidemic of obesity in developed countries, an increasing incidence of DN is being widely reported. The underlying pathogenic mechanisms mediating development and progression of human DN are still not well understood. Specifically, there is still incomplete understanding of the nature and etiology of altered protein, lipid and metabolite expression in both the glomerular and tubulointerstitial compartments during the course of human DN, and the spectrum of lesions in patients with diabetes who do not have classic or overt DN is not established because patients do not routinely undergo renal biopsy. To address these gaps in knowledge, we have assembled a team of established and experienced investigators with complementary expertise and a novel set of resources in order to investigate human DN. We will use histology-directed MALDI Imaging Mass Spectrometry (MALDI IMS), a novel imaging technology that has been validated in our preliminary studies of mouse renal tissues, to mine and phenotype proteomic, lipidomic and metabolomic changes in human DN in order to map the molecular profile of lesions that may be attributable to diabetes or to other unrecognized abnormalities in diabetic patients. We will obtain human kidney samples from a cohort of patients pre-consented for DNA analysis and linked to a de-identified electronic medical record (Synthetic Derivative, SD) and DNA samples (BioVU). Validation of a detailed phenotype of patients with existing diabetic nephropathy that continues to be updated in real time will allow detailed prospective mining of such samples.
The specific aims of the study are: 1) To create a human kidney tissue biorepository linked to a de-identified electronic medical record in order to facilitate studies of human diabetic nephropathy and other kidney diseases; 2) To determine protein, lipid, and metabolite profiles in distinct nephron segments and cell types in the human diabetic kidney using MALDI IMS and integrate the results with light and electron microscopic findings; 3) To integrate protein, lipid, and metabolite information in the diabetic glomerulus with phenotype and genotype data in order to identify specific molecular changes associated with development or progression of diabetic nephropathy; and 4) To determine potential therapeutic targets by exploring molecular mechanisms underlying the identified changes in proteins, lipids and metabolites occurring in the course of human diabetic nephropathy Our overall goal for these studies is to define the molecular basis for human diabetic nephropathy and to identify potential targets for therapy by utilizing new and powerful modalities: MALDI IMS combined with conventional microscopy and a human renal tissue biorepository linked to both a synthetic medical record and the patients' DNA.

Public Health Relevance

The proposed studies will utilize novel methods to study the biochemical changes to the kidney in response to diabetes (''diabetic nephropathy'') and will investigate the underlying mechanisms responsible for these changes. The studies will utilize novel and innovative resources and techniques and will employ a an ongoing program at Vanderbilt University (''BioVU''); a large biobank of >170;000 individuals that has access to de-identified electronic medical records and DNA. Another of the goals of this project will be to add to the capability of BioVU by developing a biorepository of human kidney tissue linked to the information already present in BioVU.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Resource-Related Research Projects (R24)
Project #
5R24DK103067-02
Application #
8928607
Study Section
Special Emphasis Panel (ZDK1-GRB-J (M5))
Program Officer
Ketchum, Christian J
Project Start
2014-09-18
Project End
2019-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
2
Fiscal Year
2015
Total Cost
$1,300,852
Indirect Cost
$459,283
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Wang, Feng; Katagiri, Daisuke; Li, Ke et al. (2018) Assessment of renal fibrosis in murine diabetic nephropathy using quantitative magnetization transfer MRI. Magn Reson Med 80:2655-2669
Li, Yan; Chung, Sungjin; Li, Zhilian et al. (2018) Fatty acid receptor modulator PBI-4050 inhibits kidney fibrosis and improves glycemic control. JCI Insight 3:
Grove, Kerri J; Lareau, Nichole M; Voziyan, Paul A et al. (2018) Imaging mass spectrometry reveals direct albumin fragmentation within the diabetic kidney. Kidney Int 94:292-302
de Caestecker, Mark; Harris, Raymond (2018) Translating Knowledge Into Therapy for Acute Kidney Injury. Semin Nephrol 38:88-97
Zhang, Ming-Zhi; Wang, Suwan; Wang, Yinqiu et al. (2018) Renal Medullary Interstitial COX-2 (Cyclooxygenase-2) Is Essential in Preventing Salt-Sensitive Hypertension and Maintaining Renal Inner Medulla/Papilla Structural Integrity. Hypertension 72:1172-1179
Zhang, Ming-Zhi; Wang, Xin; Yang, Haichun et al. (2017) Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model. J Am Soc Nephrol 28:3300-3311
Lim, Beom Jin; Yang, Jae Won; Zou, Jun et al. (2017) Tubulointerstitial fibrosis can sensitize the kidney to subsequent glomerular injury. Kidney Int 92:1395-1403
Wang, Xin; Yao, Bing; Wang, Yinqiu et al. (2017) Macrophage Cyclooxygenase-2 Protects Against Development of Diabetic Nephropathy. Diabetes 66:494-504
Zhang, Ming-Zhi; Wang, Xin; Wang, Yinqiu et al. (2017) IL-4/IL-13-mediated polarization of renal macrophages/dendritic cells to an M2a phenotype is essential for recovery from acute kidney injury. Kidney Int 91:375-386
Overstreet, Jessica M; Wang, Yinqiu; Wang, Xin et al. (2017) Selective activation of epidermal growth factor receptor in renal proximal tubule induces tubulointerstitial fibrosis. FASEB J 31:4407-4421

Showing the most recent 10 out of 26 publications