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Role of DPP4 in Kidney Inflammation and Injury

Award Number: K08DK115886
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Role of DPP4 in Kidney Inflammation and Injury - Project Summary/Abstract The incidence of chronic kidney disease (CKD) is increasing due to the ever-expanding number of people who are either obese (33%) or diabetic (9%) or both. In a significant proportion of obese-diabetic subjects, CKD may progress to end stage renal disease (ESRD) and dialysis faster than non-obese diabetic subjects. Care of ESRD patients (1% of Medicare population) consumes Medicare dollars in a disproportional manner (7%). Hence, preventing progression of CKD to ESRD is of paramount importance. Currently, the standard of care is to use medications that block/suppress activation of the renin-angiotensin system. However, these medications are not enough to stop progression to ESRD in many subjects and novel therapeutic agents are needed. DPP4 inhibitors are conveniently placed at the intersection of diabetes and CKD due to recent data showing improvement in proteinuria in diabetic patients with CKD (SAVOR-TIMI trial and animal models). Dr. Nistala and others have shown that DPP4 inhibitors may have kidney specific effects independent of blood pressure or blood sugar improvement. However, the mechanisms of DPP4 inhibitor-mediated benefits in the kidney are relatively unknown. If DPP4 inhibitors are to be used for preventing progression of kidney disease, the biological function of DPP4 in the kidney needs better understanding. Data supports the notion that DPP4 may regulate sodium absorption and albumin/oligomeric peptide endocytosis in proximal tubules of the kidney. In addition, DPP4 is a co-stimulatory molecule for T-lymphocytes, activates mononuclear cells (including macrophages and antigen presenting cells [APCs]) and may mediate inflammation based on findings from fat depots in obese and plasma from diabetes patients. Tubulointerstitial inflammation and fibrosis plays an important role in the progression of CKD in the setting of obesity and diabetes and importantly, Dr. Nistala found that DPP4 activity is increased in the kidney and expression levels are higher in the proximal tubules of obese/diabetic mice. Therefore, this project is focused on examining the role of DPP4 in the proximal tubule and kidney immune system in the setting of obesity/diabetes. The experiments are designed to address the central hypothesis that obesity- induced proximal tubule DPP4 activation incites a pro-inflammatory immune response leading to tubulointerstitial fibrosis and progression of kidney disease. To address this hypothesis, DPP4 will be activated via high sucrose/high fat (Western Diet) feeding in mice with or without DPP4 deficiency. In Aim 1, the role of Western diet in activation of DPP4 in the proximal tubule and tubular dysfunction will be studied by using proximal tubule specific deletion of DPP4. In Aim 2, the role of proximal tubule DPP4 in kidney immune system activation will be examined. In Aim 3, the role of proximal tubule DPP4-induced immune system activation in tubulointerstitial fibrosis and kidney disease progression will be studied. It is anticipated that results from this project will yield unique insights into the mechanisms of kidney injury and inflammation in obesity/diabetes with the ultimate goal of translating these findings into meaningful treatments.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $169,246 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/31/2023	NON-COMPETING CONTINUATION	$169,246
														Subtotal = $169,246

Issue Date FY: 2022 ( Subtotal = $169,246 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/19/2022	NON-COMPETING CONTINUATION	$169,246
														Subtotal = $169,246

Issue Date FY: 2021 ( Subtotal = $169,246 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/1/2021	NON-COMPETING CONTINUATION	$169,246
														Subtotal = $169,246

Issue Date FY: 2020 ( Subtotal = $169,246 )
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/22/2020	NON-COMPETING CONTINUATION	$169,246
														Subtotal = $169,246

Issue Date FY: 2019 ( Subtotal = $170,747 )
2019	2019	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/5/2019	NEW	$170,747
														Subtotal = $170,747

Grand Total All Awards = $847,731

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Role of DPP4 in Kidney Inflammation and Injury

Award Number: K08DK115886

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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