Department: Department of Pharmacology and Toxicology

Phone: (804) 828-2071

Fax: (804) 828-2117

Email: ningjun.li@vcuhealth.org

Address/Location:
Molecular Medicine Research Building, Room 3046
1220 East Broad Street
Box 980613
Richmond, Virginia

Education

• Henan Medical College, China, 1984

Research interests: Renal mechanisms of hypertension and molecular mechanisms mediating the progression of chronic kidney diseases.
Renal sphingolipids in sodium excretion blood pressure regulation. Sphingolipids were originally thought to serve as silent structural elements of the cell membrane. Recently, sphingolipid metabolites are emerging as important lipid signaling molecules. Among them, sphingosine-1- phosphate (S1P) is known to play important roles in cellular processes in various organ systems including the cardiovascular system and kidney. Five members of the S1P receptor family (S1PR1–S1PR5) have been identified. The S1PR1-3 are present in the kidneys. We have recently demonstrated that S1P1-3 receptors are prominently expressed in the renal medulla, mainly located in the collecting ducts, and that S1PR1 receptor in the renal medulla mediates a strong natriuretic effect via inhibiting epithelial Na+ channel (ENaC). Our data have shown that renal S1P receptors and its producing enzymes respond to high salt intake and that there are defects in S1P pathway in salt-sensitive hypertensive models. Interestingly, manipulation in this pathway attenuates salt-sensitive hypertension in animal models. The hypothesis to be tested is that the renal S1P pathway is a critical counterbalancing mechanism to inhibit the excessive Na+ reabsorption and that suppression of renal S1P pathway contributes to the development of salt-sensitive hypertension.

Molecular mechanism of hypertension-induced renal injury: the role of hypoxia inducible factor-1α. Hypoxia inducible factor (HIF)-1α is a transcription factor that has been shown to be up-regulated in almost all types of chronic kidney diseases (CKD). HIF-1α stimulates the collagen accumulation by activating fibrogenic factors. There is evidence suggesting that the long-term activation of HIF-1α is injurious in CKD, although upregulation of HIF-1α is protective in acute kidney injury. The coexistent hypertension plays a predominant role in the progression of CKD. Despite the findings that impaired renal autoregulation transmits the elevated renal perfusion pressure (RPP) into the renal microvasculature, causing RPP-induced renal injury in CKD, little is known regarding the molecular mechanism mediating RPP-induced injury. Our preliminary data showed that silencing of HIF-1α attenuated renal injury without effect on hypertension in a rat 5/6 renal ablation/infarction model (5/6 A/I); maintaining a normal RPP blocked the increase of renal HIF-1α and suppressed the renal injury in this CKD model, indicating that HIF-1α may mediate RPP-induced renal injury. HIF prolyl- hydroxylases (prolyl hydroxylase domain-containing proteins, PHDs) are the major enzymes to promote the degradation of HIF-1α and present in the kidneys to regulate renal HIF-1α. We recently showed that PHDs play a critical role in TGF-β- and ANG II-induced activation of HIF-1α and consequent injuries in renal cells. Further, the PHD activity is inhibited by the activation of TRPC6, a member of the Transient Receptor Potential Channels. The activation of TRPC6 is known to produce renal injury. Moreover, TRPC6 participates in the mechanical/pressure sensation in various cell types, including podocytes. Therefore, TRPC6 may be the upstream mediator that transmits the RPP stress into downstream molecular pathways to cause RPP-induced injury. The hypothesis to be tested is that the elevated RPP activates TRPC6, which inhibits PHD activity to induce HIF-1α- mediated profibrogenic genes, consequently causing renal injuries in CKD.

Other ongoing projects include: Role of sphingosine lipids in the regulation of renal function; Renal stem cell deficiency in the development of hypertension; Renal α7 nicotinic acetylcholine receptor in kidney salt handling; Renal inflammasome in salt-sensitive hypertension; Mechanism of fructose-induced salt-sensitive hypertension; Mechanism of obesity-induced salt-sensitive hypertension; Microbiota in salt intake sensing and blood pressure regulation, etc.

Several animal and cell model systems have been used such as conditional knockout mice, DOCA-salt and Dahl salt sensitive hypertensive rats, SS-13BN consomic rats, renal collecting duct cells, proximal tubule cells, medullary interstitial cells, and glomerular podocytes and 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.

Selected publications:

Wang Z, Zhu Q, Wang W, Hu J, Li PL, Yi F, Li N. Down-regulation of microRNA-429 contributes to angiotensin II-induced profibrotic effect in rat kidney. Am J Physiol Renal Physiol. 315(6):F1536-F1541, 2018.

Wang Z, Zhu Q, Yi F, Li PL, Boini KM, Li N. Infusion of valproic acid into the renal medulla activates stem cell population and attenuates salt-sensitive hypertension in Dahl S rats. Cell Physiol Biochem. 42(3):1264-1273, 2017.

Hu J, Wang W, Zhang F, Li PL, Boini KM, Yi F, Li N. Hypoxia inducible factor-1α mediates the profibrotic action of albumin in renal tubular cells. Sci Rep. 7(1):15878, 2017.

Hu J, Zhu Q, Xia M, Guo TL, Li PL, Han WQ, Li N. Transplantation of mesenchymal stem cells into the renal medulla attenuated salt-sensitive hypertension in Dahl S rat. J Mol Med (Berl). 92 (11):1139-1145, 2014.
      • Editorial Commentary: Luft FC. Mesenchymal stem cells seem too good to believe! J Mol Med (Berl). 92(11):1117-8, 2014.

Wang Z, Zhu Q, Li PL, Dhaduk R, Zhang F, Li N. Silencing of Hypoxia Inducible Factor-1α Gene Attenuated Chronic Ischemic Renal Injury in Two-Kidney One-Clip Rats. Am J Physiol Renal Physiol. 15;306(10):F1236-42, 2014.

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(1):F35-41, 2011. 
      • Editorial Commentary: Jackson EK. Role of Sphingosine-1-Phosphate in the Renal Medulla. Am J Physiol Renal Physiol. 301(1):F33-4, 2011.
 
Wang Z, Tang L, Zhu Q, Yi F, Zhang F, Li PL, Li N. Hypoxia inducible factor-1α contributes to the profibrotic action of angiotensin II in renal medullary interstitial cells. Kidney Int. 79(3):300-10, 2011.
      • Editorial Commentary: Haase VH. Angiotensin II: breathtaking in the renal medulla. Kidney Int. 79(3):269-71, 2011.

Wang Z, Zhu Q, Xia M, Li PL, Hinton SJ, Li N. Hypoxia-Inducible Factor Prolyl-Hydroxylase 2 Senses High-Salt Intake to Increase Hypoxia Inducible Factor 1α Levels in the Renal Medulla. Hypertension. 55(5):1129-36, 2010.

Xia M, Chen L, Muh RW, Li PL, Li N. Production and actions of hydrogen sulfide, a novel gaseous bioactive substance, in the kidneys. J Pharmacol Exp Ther. 329(3):1056-62, 2009.

Xia M, Li PL, Li N. 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, 2008.

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