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Promise for gene therapy in obstructive nephropathy

2004; Elsevier BV; Volume: 66; Issue: 4 Linguagem: Inglês

10.1111/j.1523-1755.2004.00984.x

1523-1755

Robert L. Chevalier,

Acute Kidney Injury Research

Obstructive nephropathy is a complex renal disorder that begins with hydrodynamic and hemodynamic responses, leading to cellular changes in all renal compartments, and finally to interstitial fibrosis and tubular atrophy. Over the past three decades, numerous physiologic and molecular mechanisms that underlie these observations have been elucidated. Much attention was initially focused on renal vasoconstriction resulting from ureteral obstruction, and subsequent studies revealed a role for angiotensin II, thromboxanes, and endothelin1Chevalier R.L. Roth J.A. Obstructive uropathy, chapter 55,.in: Avner E.D. Harmon W.E. Niaudet P. Pediatric Nephrology. 5th ed. Lippincott Williams and Wilkins, Philadelphia2004: 1049-1076Google Scholar. As with most regulatory processes, counteracting forces (in the form of vasodilators) have been shown to modulate the effects of endogenous vasoconstrictors in the hydronephrotic kidney. In 1992, we reported that endogenous endothelial-relaxing factor (now identified as nitric oxide) attenuates the vasoconstriction resulting from acute unilateral ureteral obstruction (UUO) in the rat2Chevalier R.L. Thornhill B.A. Gomez R.A. EDRF modulates renal hemodynamics during unilateral ureteral obstruction in the rat.Kidney Int. 1992; 42: 400-406Abstract Full Text PDF PubMed Scopus (50) Google Scholar. In a recent report, arginine infusion was shown to increase glomerular filtration rate (GFR) of both obstructed and contralateral kidneys, which is accompanied by an increase in renal inducible NOS (iNOS) activity3Ito K. Chen J. Vaughan Jr, E.D. et al.Dietary L-arginine supplementation improves the glomerular filtration rate and renal blood flow after 24 hours of unilateral ureteral obstruction in rats.J Urol. 2004; 171: 926-930Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar. Either angiotensin inhibition or stimulation of endogenous NOS with arginine could increase renal NOS activity, which appears to suppress macrophage infiltration, myofibroblast transformation, and progression of interstitial fibrosis following UUO4Morrissey J.J. Ishidoya S. McCracken R. Klahr S. Nitric oxide generation ameliorates the tubulointerstitial fibrosis of obstructive nephropathy.J Am Soc Nephrol. 1996; 7: 2202-2212PubMed Google Scholar. Subsequent studies showed that targeted disruption of iNOS aggravates transforming growth factor-β1 (TGF-β1) expression and macrophage accumulation following UUO in mice5Hochberg D. Johnson C.W. Chen J. et al.Interstitial fibrosis of unilateral ureteral obstruction is exacerbated in kidneys of mice lacking the gene for inducible nitric oxide synthase.Lab Invest. 2000; 80: 1721-1728Crossref PubMed Scopus (60) Google Scholar. These observations underscore the cellular role of nitric oxide in the hydronephrotic kidney, with evidence for both anti-inflammatory and antifibrotic effects. Recently, arginine infusions in dogs with 18 hours of UUO were shown to increase renal blood flow, leading to the conclusion that a lack of substrate may contribute to the profound vasoconstriction resulting from chronic UUO6Felsen D. Schulsinger D. Gross S.S. et al.Renal hemodynamic and ureteral pressure changes in response to ureteral obstruction: The role of nitric oxide.J Urol. 2003; 169: 373-376Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar. Chronic UUO in mice leads to a progressive reduction in the production of iNOS by the obstructed kidney, and tubular apoptosis is even more severe following UUO in mice lacking the gene for iNOS7Miyajima A. Chen J. Poppas D.P. et al.Role of nitric oxide in renal tubular apoptosis of unilateral ureteral obstruction.Kidney Int. 2001; 59: 1290-1303Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar. Mechanical stretch of tubular epithelial cells due to tubular dilatation appears to be a major factor contributing to apoptosis following UUO, and axial strain on cultured tubular cells increases iNOS expression8Miyajima A. Chen J. Kirman I. et al.Interaction of nitric oxide and transforming growth factor-β1 induced by angiotensin II and mechanical stretch in rat renal tubular epithelial cells.J Urol. 2000; 164: 1729-1734Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar. Moreover, inhibition of endogenous iNOS increases stretch-induced apoptosis in rat renal tubular cells7Miyajima A. Chen J. Poppas D.P. et al.Role of nitric oxide in renal tubular apoptosis of unilateral ureteral obstruction.Kidney Int. 2001; 59: 1290-1303Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar. Experimental manipulation of processes responsible for the initiation and progression of obstructive nephropathy has involved a number of techniques, including the administration of growth factors, inhibitors, and antisense oligonucleotides. Since most clinical obstructive nephropathy is a chronic process, there is considerable interest in developing long-term treatment options, such as gene therapy. Hepatocyte growth factor (HGF), which has antifibrotic actions in the hydronephrotic kidney9Gao X. Mae H. Ayabe N. et al.Hepatocyte growth factor gene therapy retards the progression of chronic obstructive nephropathy.Kidney Int. 2002; 62: 1238-1248Abstract Full Text Full Text PDF PubMed Google Scholar, is an attractive candidate for gene therapy. The transduction of skeletal muscle with the HGF gene using liposomes containing the hemagglutinating virus of Japan has been shown to suppress macrophage infiltration, tubular apoptosis, interstitial fibrosis, and tubular atrophy following chronic UUO in the rat9Gao X. Mae H. Ayabe N. et al.Hepatocyte growth factor gene therapy retards the progression of chronic obstructive nephropathy.Kidney Int. 2002; 62: 1238-1248Abstract Full Text Full Text PDF PubMed Google Scholar. A second report of HGF gene transfer by intravenous injection of plasmid vector into mice with chronic UUO demonstrates a synergistic protective effect in combination with angiotensin II blockade10Yang J. Dai C. Liu Y. Hepatocyte growth factor gene therapy and angiotensin II blockade synergistically attenuate renal interstitial fibrosis in mice.J Am Soc Nephol. 2002; 13: 2464-2477Crossref PubMed Scopus (129) Google Scholar. The salutary effects include a reduction in myofibroblast transformation, decreased TGF-β1 expression, and preservation of renal mass10Yang J. Dai C. Liu Y. Hepatocyte growth factor gene therapy and angiotensin II blockade synergistically attenuate renal interstitial fibrosis in mice.J Am Soc Nephol. 2002; 13: 2464-2477Crossref PubMed Scopus (129) Google Scholar. In this issue of Kidney International, Ito et al demonstrate improved renal function by intraureteral administration of the iNOS gene in rats with 24 hours' UUO11Ito K. Chen J. Khodadadian J.J. et al.Liposome-mediated transfer of nitric oxide synthase gene improves renal function in ureteral obstruction in rats.Kidney Int. 2004; 66: 1365-1375Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar. The intramuscular route of administration was not used because myocyte expression of intracellular proteins such as iNOS would not likely affect the kidney. In this very well controlled study using cationic liposomes as the vehicle, iNOS was localized to collecting ducts, distal tubules, and glomeruli. Importantly, renal expression of iNOS and urinary NO2/NO3 remained elevated more than 30 days after transfection (previous reports of kidney-targeted viral-mediated delivery of genes have not shown long-term expression)11Ito K. Chen J. Khodadadian J.J. et al.Liposome-mediated transfer of nitric oxide synthase gene improves renal function in ureteral obstruction in rats.Kidney Int. 2004; 66: 1365-1375Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar. While iNOS transduction was performed seven days prior to ureteral obstruction, and functional studies were performed after only 24 hours of UUO, the authors indicate that longer term studies of morphologic effects of iNOS transduction are to follow. Of note, iNOS gene expression was increased also in the contralateral kidney, and some glomerular expression of the transfected iNOS appeared in glomeruli of the intact contralateral kidney. Despite this, the lack of effect of transfected iNOS on renal function in nonoperated control animals suggests that a physiologic response is elicited only in the pathologic kidney. This is a promising study, indicating that liposome-mediated intraureteral transfer of the iNOS gene can have significant salutary effects in a model of obstructive nephropathy. The information gained by augmentation of iNOS gene expression complements studies of UUO in iNOS knockout mice. However, many hurdles remain before this approach becomes a potential therapeutic modality. The cellular and physiologic roles of nitric oxide in the hydronephrotic kidney are highly complex. For example, whether nitric oxide acts as an antiapoptotic or a proapoptotic modulator may depend on its local concentration, which can be difficult to regulate with intraureteral injection of the transfected liposome12Chung H.T. Pae H.O. Choi B.M. et al.Nitric oxide as a bioregulator of apoptosis.Biochem Biophys Res Commun. 2001; 282: 1075-1079Crossref PubMed Scopus (445) Google Scholar. In addition, nitric oxide appears to mediate the stimulation of TGF-β1 by angiotensin II (a fibrogenic pathway), and TGF-β1, in turn, inhibits iNOS8Miyajima A. Chen J. Kirman I. et al.Interaction of nitric oxide and transforming growth factor-β1 induced by angiotensin II and mechanical stretch in rat renal tubular epithelial cells.J Urol. 2000; 164: 1729-1734Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar. For optimal therapeutic efficacy, the iNOS gene may need to be delivered to specific intrarenal compartments or cell types, and during defined intervals. More answers are certain to be forthcoming from this productive laboratory that has taught us much about the intricacies of nitric oxide in obstructive nephropathy.