 |
|
 |
Ningjun Li,
M.D. |
Education: Henan Medical College, China, 1984
Research interests: Renal mechanisms of hypertension and the related kidney damages. Current research focus: Renal medullary HIF prolyl hydroxylases and salt sensitivity of blood pressure.
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 (HIF)-1alpha. HIF-1alpha is also highly expressed in renal medulla and
responds to high salt intake. Recently, HIF prolyl hydroxylase domain-containing
enzymes (PHDs) 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 test is
that PHDs 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
alters 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 that
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,
then 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, Li N. A novel lipid natriuretic factor in
the renal medulla: sphingosine-1-phosphate. Am J Physiol Renal Physiol.
301:F35-41, 2011
· Editorial Focus: Jackson EK. Role of
Sphingosine-1-Phosphate in the Renal Medulla. Am J Physiol Renal Physiol.,
301(1):F33-4.
Wang Z, Tang L, Zhu Q, Yi F, Zhang F, Li PL, Li N.
Hypoxia inducible factor-1alpha contributes to the profibrotic action of
angiotensin II in renal medullary interstitial cells. Kidney Int. 2011,
79:300-10.
· Editorial Commentary: Haase VH. Angiotensin II:
breathtaking in the renal medulla. Kidney Int. 2011, 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. J Pharmacol Exp Ther. 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. Am J
Physiol Regul Integr Comp Physiol. 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. Circ Res.
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. Am J
Nephrol 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. Am J Physiol: Renal Physiol.
282: F1111-F1119.