The specialized microenvironment where the stem cells reside in vivo is termed stem cell niche, which is critical for the maintenance, self-renewal and differentiation of stem cells by providing extrinsic regulators. Renal medulla has recently been identified as a niche for adult kidney stem cells and these renal medullary stem cells are importantly involved in the normal structural and functional maintenance in the renal medulla. It is well known that the renal medulla plays an important role in the regulation of sodium excretion and that dysfunctions in the renal medulla are involved in salt-sensitive hypertension. We wondered whether the stem cell niche in the renal medulla, through regulating the behavior of stem cells, contributes to the maintenance of normal functional integrity in this kidney region and thereby to the long-term control of arterial blood pressure, and whether salt-sensitive hypertension is associated with the impairment of stem cell resource or niche in the renal medulla. In preliminary studies, we found that the level of an important stem cell niche factor, fibroblast growth factor-2 (FGF2), the number of CD133 positive stem cells and their responses to high salt intake were significantly decreased in the renal medulla in Dahl salt-sensitive hypertensive (Dahl S) rats compared with normotensive rats. It was also found that the decreased FGF2 level was associated with a deficiency in hypoxia-inducible factor (HIF)-1? and that improving stem cell niche function decreased pro-inflammatory factors in the renal medulla and attenuated salt-sensitive hypertension in Dahl S rats. These data indicate that a defect of stem cell niche may lead to abnormal generation, mobilization and differentiation of stem cells in the renal medulla and thereby lead to a failure of maintenance of renal medullary structural and functional integrity in face to high salt challenge, ultimately resulting in salt-sensitive hypertension in Dahl S rats. Based on these findings, we hypothesize that the renal medullary stem cell niche plays a critical role in the regulation of renal medullary function and the defect of such stem cell niche contributes to the development of hypertension in Dahl S rats. To test this hypothesis, we will first determine whether FGF2 regulation of stem cell behavior in the renal medulla contributes to the regulation of renal medullary function and whether a defect of this stem cell niche factor mediates the development of salt-sensitive hypertension in Dahl S rats. We will then explore the mechanisms causing the defect of the stem cell niche in the renal medulla of Dahl S rats by determining whether impaired HIF-1? and consequent decreases in FGF-2 levels contribute to the deficiency of this medullary stem cell niche. Finally, we will determine how the defect of renal medullary stem cell niche produces renal medullary dysfunction and hypertension in Dahl S rats, focusing on the insufficiency of stem cell-mediated anti-inflammatory actions in the renal medulla. The results from these proposed studies will define an important cellular/molecular mechanism mediating renal medullary adaptation to high salt intake and provide new insights into the stem cell-associated pathogenesis of salt-sensitive hypertension.

Public Health Relevance

A deep kidney region called the renal medulla has been identified as a stem cell niche, a specialized microenvironment where the adult kidney stem cells reside. The important niche function to regulate stem cell behavior maintains the renewal of kidney cells in the renal medulla, which is critical for the kidney to handle salt and body fluid balance and thereby to keep the arterial blood pressure normal. Defect of stem cell niche causes malfunction of these stem cells and leads to high blood pressure. All these will be clarified in this proposal. When the studies planed in this grant application are completed, new therapeutic strategies associated with stem cell activation could be developed for the treatment of high blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106042-04
Application #
8584315
Study Section
Special Emphasis Panel (ZRG1-VH-E (02))
Program Officer
OH, Youngsuk
Project Start
2011-01-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$336,375
Indirect Cost
$111,375
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Hu, Junping; Zhu, Qing; Xia, Min et al. (2014) Transplantation of mesenchymal stem cells into the renal medulla attenuated salt-sensitive hypertension in Dahl S rat. J Mol Med (Berl) :
Zhu, Qing; Hu, Junping; Han, Wei-Qing et al. (2014) Silencing of HIF prolyl-hydroxylase 2 gene in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats. Am J Hypertens 27:107-13
Wang, Zhengchao; Zhu, Qing; Li, Pin-Lan et al. (2014) Silencing of hypoxia-inducible factor-1? gene attenuates chronic ischemic renal injury in two-kidney, one-clip rats. Am J Physiol Renal Physiol 306:F1236-42
Han, Wei-Qing; Zhu, Qing; Hu, Junping et al. (2013) Hypoxia-inducible factor prolyl-hydroxylase-2 mediates transforming growth factor beta 1-induced epithelial-mesenchymal transition in renal tubular cells. Biochim Biophys Acta 1833:1454-62
Zhu, Qing; Wang, Zhengchao; Xia, Min et al. (2011) Silencing of hypoxia-inducible factor-1? gene attenuated angiotensin II-induced renal injury in Sprague-Dawley rats. Hypertension 58:657-64
Wang, Zhengchao; Tang, Lin; Zhu, Qing et al. (2011) Hypoxia-inducible factor-1? contributes to the profibrotic action of angiotensin II in renal medullary interstitial cells. Kidney Int 79:300-10
Zhu, Qing; Xia, Min; Wang, Zhengchao et al. (2011) A novel lipid natriuretic factor in the renal medulla: sphingosine-1-phosphate. Am J Physiol Renal Physiol 301:F35-41