Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
1998-12-15
2001-11-13
LeGuyader, John L. (Department: 1635)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
C435S007100
Reexamination Certificate
active
06316258
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method for reducing accumulation of excess extracellular matrix induced by TGF&bgr; in a subject by inhibiting renin, and more particularly to the prevention and treatment of fibrotic disease resulting from accumulation of excess extracellular matrix using renin inhibitory agents and compositions including renin inhibitory agents and TGF&bgr; inhibitory agents.
BACKGROUND OF THE INVENTION
Overproduction of transforming growth factor (TGF)&bgr; clearly underlies tissue fibrosis caused by excess deposition of extracellular matrix resulting in disease. TGF&bgr;'s fibrogenic action results from simultaneous stimulation of matrix protein synthesis, inhibition of matrix degradation and enhanced integrin expression that facilitates extracellular matrix (ECM) assembly. Overproduction of TGF&bgr; has been demonstrated in glomerulonephritis, diabetic nephropathy and hypertensive glomerular injury. Suppression of the production of ECM and prevention of accumulation of mesangial matrix in glomeruli of glomerulonephritic rats has been demonstrated by intravenous administration of neutralizing antibodies specific for TGF&bgr; (Border et al., Nature 346:371-374 (1990)) or administration of purified decorin (Border et al., Nature 360:361-364 (1992)) and by introduction of nucleic acid encoding decorin, a TGF&bgr;-inhibitory agent, into a rat acute mesangial model of glomerulonephritis (Isaka et al., Nature Med. 2:418-423 (1996)).
Renin is an aspartyl proteinase synthesized by juxtaglomerular kidney cells and mesangial cells in humans and rats. (Chansel et al., Am. J. Physiol. 252:F32-F38 (1987) and Dzau and Kreisberg, J. Cardiovasc. Pharmacol. 8(Suppl 10):S6-S10 (1986)). Renin plays a key role in the regulation of blood pressure and salt balance. Its major source in humans is the kidney where it is initially produced as preprorenin. Signal peptide processing and glycosylation are followed by secretion of prorenin and its enzymatically active form, mature renin. The active enzyme triggers a proteolytic cascade by cleaving angiotensinogen to generate angiotensin I, which is in turn converted to the vasoactive hormone angiotensin II by angiotensin converting enzyme (“ACE”).
The sequence of the human renin gene is known (GenBank entry M26901). Recombinant human renin has been synthesized and expressed in various expression systems (Sielecki et al., Science 243:1346-1351 (1988), Mathews et al., Protein Expression and Purification 7:81-91 (1996)). Inhibitors of renin are known (Rahuel et al., J. Struct. Biol. 107:227-236 (1991); Badasso et al., J. Mol. Biol. 223:447-453 (1992); and Dhanaraj et al., Nature 357:466-472 (1992)) including an orally active renin inhibitor in primates, Ro 42-5892 (Fischli et al., Hypertension 18:22-31 (1991)). Renin-binding proteins and a cell surface renin receptor on human mesangial cells have been identified (Campbell and Valentijn, J. Hypertens. 12:879-890 (1994), Nguyen et al., Kidney Internat. 50:1897-1903 (1996) and Sealey et al., Amer. J. Hyper. 9:491-502 (1996)).
The renin-angiotensin system (RAS) is a prototypical systemic endocrine network whose actions in the kidney and adrenal glands regulate blood pressure, intravascular volume and electrolyte balance. In contrast, TGF&bgr; is considered to be a typical cytokine, a peptide signaling molecule whose multiple actions on cells are mediated in a local or paracrine manner. Recent data however, indicate that there is an intact RAS in many tissues whose actions are entirely paracrine and TGF&bgr; has wide-ranging systemic (endocrine) effects. Moreover, RAS and TGF&bgr; act at various points to regulate the actions of one another.
In a systemic response to an injury such as a wound, the RAS rapidly generates AII that acts by vasoconstriction to maintain blood pressure and later stimulates the secretion of aldosterone, resulting in an increase in intravascular volume. In the wound, TGF&bgr; is rapidly released by degranulating platelets and causes a number of effects including: 1) autoinduction of the production of TGF&bgr; by local cells to amplify biological effects; 2) chemoattraction of monocyte/macrophages that debride and sterilize the wound and fibroblasts that begin synthesis of ECM; 3) causing deposition of new ECM by simultaneously stimulating the synthesis of new ECM, inhibiting the proteases that degrade matrix and modulating the numbers of integrin receptors to facilitate cell adhesion to the newly assembled matrix; 4) suppressing the proinflammatory effects of interleukin-1 and tumor necrosis factor; 5) regulating the action of platelet derived growth factor and fibroblast growth factor so that cell proliferation and angiogenesis are coordinated with matrix deposition; and 6) terminating the process when repair is complete and the wound is closed (Border and Noble, Scientific Amer. Sci. & Med. 2:68-77 (1995)).
Interactions between RAS and TGF&bgr; occur at both the systemic and molecular level. It has been shown that TGF&bgr;'s action in causing ECM deposition in a healing wound is the same action that makes TGF&bgr; a powerful fibrogenic cytokine. (Border and Noble, New Engl. J. Med. 331:1286-1292 (1994); and Border and Ruoslahti, J. Clin. Invest. 90:107(1992)). Indeed, it is the failure to terminate the production of TGF&bgr; that distinguishes normal tissue repair from fibrotic disease. RAS and TGF&bgr; co-regulate each other's expression. Thus, both systems may remain active long after an emergency response has been terminated, which can lead to progressive fibrosis. The kidney is particularly susceptible to overexpression of TGF&bgr;. The interrelationship of RAS and TGF&bgr; may explain the susceptibility of the kidney to TGF&bgr; overexpression and why pharmacologic suppression of RAS or inhibition of TGF&bgr; are both therapeutic in fibrotic diseases of the kidney. (Noble and Border, Sem. Nephrol., supra and Border and Noble, Kidney Int. 51:1388-1396 (1997)).
Activation of RAS and generation of angiotensin II (AII) are known to play a role in the pathogenesis of hypertension and renal and cardiac fibrosis. TGF&bgr; has been shown to be a powerful fibrogenic cytokine, acting simultaneously to stimulate the synthesis of ECM, inhibit the action of proteases that degrade ECM and increasing the expression of cell surface integrins that interact with matrix components. Through these effects, TGF&bgr; rapidly causes the deposition of excess ECM. AII infusion strongly stimulates the production and activation of TGF&bgr; in the kidney. (Kagami et al., J. Clin. Invest. 93:2431-2437 (1994)). Angiotensin II also upregulates TGF&bgr; production and increases activation when added to cultured vascular smooth muscle cells (Gibbons et al, J. Clin. Invest. 90:456-461 (1992)) and this increase is independent of pressure (Kagami et al., supra). Blockade of AII reduces TGF&bgr; overexpression in kidney and heart, and it is thought that TGF&bgr; mediates renal and cardiacfibrosis associated with activation of RAS (Noble and Border, Sem. Nephrol. 17(5):455-466 (1997)). Blockade of AII using inhibitors of ACE slow the progression of renal fibrotic disease (see, e.g., Anderson et al., J. Clin. Invest. 76:612-619 (1985) and Noble and Border, Sem. Nephrol. 17(5):455-466 (1997)). What is not clear is whether angiotensin blockade reduces fibrosis solely through controlling glomerular hypertension and thereby glomerular injury, or whether pressure-independent as well as pressure-dependent mechanisms are operating. While ACE inhibitors have been shown to slow the progress of fibrotic diseases, they do not halt disease and TGF&bgr; levels remain somewhat elevated.
Thus, RAS and TGF&bgr; can be viewed as powerful effector molecules that interact to preserve systemic and tissue homeostasis. The response to an emergency is that RAS and TGF&bgr; become activated. Continued activation may result in chronic hypertension and progressive tissue fibrosis leading to organ failure. Because of the interplay between the RAS and TGF&bgr;, and the effects of this interplay o
Border Wayne A.
Noble Nancy A.
Epps Janet
LeGuyader John L.
Mandel & Adriano
University of Utah
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