Ningjun Li, M.D.
Molecular Medicine Research Building, Room 3046
1220 East Broad Street
Richmond, Virginia 23298-0613
Phone: (804) 828-2071
Fax: (804) 828-2117
- Henan Medical College, China, 1984
- Renal mechanisms of hypertension and the related kidney damages
Renal medullary HIF prolyl hydroxylases and salt sensitivity of blood pressure
Many enzymes, which produce anti-hypertensive factors such as nitric oxide synthase, cyclooxygenase-2 and hemeoxygenase-1, are highly expressed in renal medulla and participate in renal adaptation to high salt intake. The genes encoding these adaptive enzymes are oxygen-sensitive genes that are regulated by hypoxia inducible factor-1alpha. HIF-1alpha is also highly expressed in renal medulla and responds to high salt intake. Recently, HIF prolyl hydroxylase domain-containing enzymes have been identified as oxygen sensors to regulate HIF-1alpha levels. Our preliminary data showed that PHDs were predominantly present in renal medulla and regulated by high salt diet, and modification of PHD/HIF-1alpha functions in the renal medulla significantly affect salt handling. Therefore, activation of PHD/HIF-1alpha-mediated gene expression may represent an important adaptive mechanism in the renal medulla in response to high salt intake. The hypothesis to be tested is that PHD regulation of HIF-1alpha-mediated gene transcription controls the expression of oxygen-sensitive genes, which mediates salt adaptation in the renal medulla and participates in the control of arterial blood pressure. The aims of this project are, first, to determine whether chronic renal adaptive response to high salt intake is associated with PHD/HIF-1alpha pathway in the renal medulla of normal rats, then to determine whether manipulates PHD/HIF-1alpha pathway in the renal medulla alter salt sensitivity of arterial blood pressure and finally to examine whether dysfunction in PHD/HIF-1alpha pathway in the renal medulla contributes to the salt-sensitive hypertension in Dahl S rats and explore the mechanisms responsible for the deficiency of PHD/HIF-1alpha in these rats.
Renal medullary stem cell niche in salt-sensitive hypertension
Stem cell niche, where the stem cells reside in vivo, provides microenvironment and extrinsic signals that determine the maintenance, self-renewal and differentiation of stem cells. The renal medulla is a niche for adult kidney stem cells and these renal medullary stem cells importantly participate in the structural and functional maintenance and repair of renal medullary cells. Given the fact that the renal medulla plays an important role in the regulation of sodium excretion and long-term blood pressure, the function of stem cell niche in the renal medulla may contribute to the maintenance of normal cell homeostasis and functional integrity in this kidney region and, thereby, to the long-term regulation of arterial blood pressure. Our preliminary data showed 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 of Dahl salt-sensitive hypertensive (Dahl S) rats compared with normotensive rats. It was also found that the decreased FGF2 level was associated with HIF-1alpha deficiency in the renal medulla, and improving stem cell niche function decreased pro-inflammatory factors in the renal medulla and attenuated salt-sensitive hypertension in Dahl S rats. It is hypothesized 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. The aims of this project are, first, to determine whether the abnormality of renal medullary stem cell niche contributes to the development of salt-sensitive hypertension in Dahl S rats, to explore the mechanisms causing the defect of the stem cell niche in the renal medulla of Dahl S rats and, finally, to determine how the defect of renal medullary stem cell niche produces renal medullary dysfunction and hypertension in Dahl S rats.
Other projects include the role of sphingolipids in the regulation of renal function, epigenetic gene regulation in the control of renal medullary function and mechanism of fibrogenesis in chronic renal diseases.
Several animal and cell model systems have been used such as Dahl salt sensitive hypertensive rats, SS-13BN consomic rats, renal medullary interstitial cells, renal tubular cells and glomerular mesangial cells. Many advanced approaches are utilized including telemetry blood pressure recording, Laser-Doppler blood flowmeter, servo-control of renal perfusion pressure, in vivo molecular imaging, ESR spectrometry, fluorescent microscopic imaging, confocal microscopy, LC/MS, real-time PCR, in vivo gene manipulation in the kidneys, etc.
Zhu Q, Xia M, Wang Z, Li PL and Li N. (2011) A novel lipid natriuretic factor in the renal medulla: sphingosine-1-phosphate. American Journal of Physiology – Renal Physiology. 301:F35-41.
- Editorial focus: Jackson EK. Role of Sphingosine-1-Phosphate in the Renal Medulla. American Journal of Physiology – Renal Physiology. 301(1):F33-4.
Wang Z, Tang L, Zhu Q, Yi F, Zhang F, Li PL and Li N. (2011) Hypoxia inducible factor-1alpha contributes to the profibrotic action of angiotensin II in renal medullary interstitial cells. Kidney International. 79:300-10.
- Editorial commentary: Haase VH. (2011) Angiotensin II: breathtaking in the renal medulla. Kidney International. Feb;79(3):269-71.
Wang Z, Zhu Q, Xia M, Li PL, Hinton SJ and Li N. (2010) Hypoxia-inducible factor prolyl-Hydroxylase 2 senses high-salt intake to increase hypoxia inducible factor-1apha levels in the renal medulla. Hypertension. 55(5):1129-36.
Xia M, Chen L, Muh RW, Li PL and Li N. (2009) Production and actions of hydrogen sulfide, a novel gaseous bioactive substance, in the kidneys. Journal of Pharmacology and Experimental Therapeutics. 329(3):1056-62.
Xia M, Li PL and Li N. (2008) Telemetric signal-driven servo-control of renal perfusion pressure in acute and chronic rat experiments. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology. 295(5):R1494-501.
Li N, Chen L, Yi F, Xia M and Li PL. (2008) Salt-sensitive hypertension induced by decoy of transcription factor HIF-1aplha in the renal medulla. Circulation Research. 102(9):1101-8.
Yi F, Santos EA, Xia M, Chen QZ, Li PL and Li N. (2007) Podocyte injury and glomerulosclerosis in hyperhomocysteinemic rats. American Journal of Nephrology. 30;27(3):262-268.
Li N, Yi F, Santos EA, Donley DK and Li PL. (2007) Role of renal medullary heme oxygenase in the pressure natriuresis and long-term control of arterial blood pressure. Hypertension. 49(1):148-54.
Li N, Yi FX, Spurrier JL, Bobrowitz CA and Zou AP. (2002) Production of superoxide through NADH oxidase in thick ascending limb of Henle’s loop in rat kidney. American Journal of Physiology – Renal Physiology. 282: F1111-F1119.