Juxtaglomerular (JG) cells, renin expressing cells of the renal afferent arterioles, have been described as modified vascular smooth muscle cells (VSMC). In response to prolonged stimulation, the number of renin producing cells in the JG afferent arterioles increases significantly. This phenomenon, known as JG cell hyperplasia, is thought to involve phenotypic change of afferent arteriole VSMC to become renin producing cells. However, recent studies have demonstrated that renin progenitor cells (RPC) can be detected in the mesenchyme of the prevascular metanephric kidney. These RPC are incorporated into the afferent arterioles of the embryonic kidney, become JG renin producing cells and acquire smooth muscle markers. Our recent data support these findings and demonstrate that adult mesenchymal stem cells (MSC) can be induced into renin synthesizing JG-like cells in vitro. Furthermore, MSC-like cells (characterized by CD44 and c-kit immunoreactivity) can be isolated from the adult kidney and can differentiate to express renin. Moreover, we have observed that JG cells undergoing hyperplasia in vivo (in response to low sodium diet and captopril) exhibit co-staining for renin, BrdU, CD44+ and c-kit+. Taken together, these data have led us to hypothesize that: 1) MSCs are precursors of JG renin producing cells, 2) MSC-like cells exist in the adult kidney in vivo and undergo proliferation and differentiation under intense stimulation and contribute to JG cell hyperplasia, and 3) these cells in the adult kidney may either be resident RPC or originate extrarenally. To examine these hypotheses, four specific aims will be undertaken: 1) we will first confirm that renin cells derived from MSCs in culture possess authentic JG cell characteristics;2) we will inject MSCs into mouse blastocysts and follow their fate in the kidney as they become renin expressing cells of the afferent arteriole during development and in the pathobiology of JG hyperplasia in the adult animal;3) we will further demonstrate that RPC with MSC characteristics exist in the kidney and that these cells can become JG renin cells and participate in JG hyperplasia;and 4) we will determine the source of these RPC in the adult kidney i.e. resident intrarenally vs. originating extrarenally such as the bone marrow. These experiments should lead to a greater understanding of the mechanisms of JG hyperplasia and the regulation of renin expression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035610-25
Application #
7769524
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Thrasher, Terry N
Project Start
1985-09-30
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
25
Fiscal Year
2010
Total Cost
$458,102
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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