John P. Middleton, MD

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Services

• Kidney Care
• Transplants

Department / Division:
Medicine / Nephrology

Address:
DUMC 3014
Durham, NC 27710

Appointment Telephone:
919-668-7630

Office Telephone:
919-660-6860

Fax Telephone:
919-684-4476

• MD, Medical College of Virginia, 1983

• Internal Medicine, University of Texas Medical Branch, 1986

• Nephrology, Duke University Medical Center, 1989

Clinical Interests:
Hypertension, general nephrology, progressive renal diseases, ESRD

Research Interests:
I. The sodium pump in the kidney assumes a uniques role in determining sodium balance and blood pressure.  My laboratory has been concerned with the cellular mechanisms for modifying solute reabsorption and the sodium pump (Na/K ATPase) in renal epithelial cells, specifically regulation of the sodium pump in the kidney by membrane receptors and signal transduction pathways.  Due to the critical role for the NA/K ATPase in salt reabsorption, these mechanisms have potential to play a role in the clinical problem of essential hypertension.

II. My laboratory has been involved with regulation of the renal sodium pump by receptors at the post-translational level.  This work provided the first evidence that species of protein kinase C participate in phosphorylation and rapid inhibition of Na/K ATPAse transport activity in the intact renal cell.  More recently we extended this observation by demonstrating that the calcium-independent isozyme of PKC can have specific action of inhibiting Na?K ATPAse .  Recently we took advantage of a transgenic mouse model that is deficient in this type 1a receptor for angiotensin II to examine physiologic modification of renal Na/K ATPAse.  Mice with mutation of the AT1A receptor demonstrate: !) a decrease in renal Na?K ATPAse activity; 2) a prominent decrease in Na/K ATPase alpha subunit gene expression; 3) a selective effect on abundance of alpha polypeptide in renal cortex; and 4) diminished blood pressure compared to control mice.  These studies demonstrate a unique effect on regulation of renal tubular Na?K ATPase by the angiotensin receptor subtype.  These exciting observations will be extended in two directions in the immediate future.  First, further studies will be performed in the intact animals to characterize the response and to determine the mechanism for control of the renal sodium pump.  Second, studies will be designed to examine the cellular mechanism for regulation of the sodium pump by the AT1A receptor in renal epithelia.

III. No clinical trials are underway at present.

IV. Recent observations from my laboratory demonstrate that membrane receptors expressed in vivo by renal epithelial cells have a potent effect on Na/K ATPase, sodium balance, and blood pressure.  I am  not getting national recognition in the field of signal transduction and renal solute transport.  I am currently preparing an invited review on this topic..

V. Key words: Na,K)-adenosine triphosphatase,  ion transport, signal transduction; blood pressure; kidney; angiotensin; sodium

Representative Publications:
Fitz JG, Sostman AH, Middleton JP: Regulation of cation channels in liver cells by intracellular calcium and protein kinase C. Am. J. Physiol. 266:G677-G684, 1994. (1994)

Middleton JP, Mangel AW, Bassavappa S, Fitz, G: Nucleotide receptors regulate membrane ion transport in renal epithelial cells. Am. J. Physiol. 264:F867-F873, 1993. (1993)

Middleton JP, Kahn W, Collinsworth G, Hannun Y, Medford R: Heterogeneous regulation of Na+?K+ ATPAse in renal epithelial cells by protein kinase C. J.Biol. Chem. 268:15958-15964, 1993. (1993)

Middleton JP, Raymond JR, Whorton AR, Dennis VW: Short-term regulation of Na+/K+ ATPAse by recombinant human 5-HT1A receptor expressed in HeLa cells. J. Clin. Invest. 86:1799-1805, 1990. (1990)

Middleton JP. Doctor B, Misra R, Oliverio M, McCormack M, Best V, Mandel L, Smithies O, Coffman TM: Modification of renal Na?K ATPAse in mice deficient in the AT1A angiotensin receptor. (Submitted)