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      Fibrogenic Effects of Cyclosporin A on the Tubulointerstitium: Role of Cytokines and Growth Factors

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          The clinical utility of cyclosporin A (CyA) as an immunosuppressive agent has been significantly limited by the frequent occurrence of chronic nephrotoxicity, characterised by tubular atrophy, interstitial fibrosis and progressive renal impairment. The pathogenesis of this condition remains poorly understood, but has been postulated to be due to either direct cytotoxicity or indirect injury secondary to chronic renal vasoconstriction. Using primary cultures of human proximal tubule cells (PTCs) and renal cortical fibroblasts (CFs) as an in vitro model of the tubulointerstitium, we have been able to demonstrate that clinically relevant concentrations of CyA are directly toxic to these cells and promote fibrogenesis by a combination of suppressed matrix metalloproteinase activity and augmented fibroblast collagen synthesis. The latter effect occurs secondary to the ability of CyA to stimulate autocrine secretion of insulin-like growth factor-I by CFs and paracrine secretion of transforming growth factor-β<sub>1</sub> by PTCs. Many of these pro-fibrotic mechanisms are completely reversed by concurrent administration of the angiotensin-converting enzyme inhibitor, enalaprilat, which has proven efficacy in preventing chronic CyA nephropathy in vivo. These studies highlight the unique potential that human renal cell cultures offer for studying the role of local cytokine networks in tubulointerstitial disease and for developing more effective treatment strategies which specifically target fibrogenic growth factor activity following nephrotoxic injuries.

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          TGF-beta 1 dissociates human proximal tubule cell growth and Na(+)-H+ exchange activity.

          Stimulation of proximal tubule cell (PTC) growth in a variety of physiological and pathological renal conditions is preceded by increased renal production of transforming growth factor-beta 1 (TGF-beta 1) and by augmented tubular sodium transport via activated sodium hydrogen exchange (NHE). Since TGF-beta 1 has been shown to be an important paracrine and autocrine regulator of PTC growth, the hypothesis that TGF-beta 1 modulates basal and mitogen-stimulated PTC growth via an effect on NHE activity was examined. Confluent, quiescent, human PTC were incubated for 24 hours in serum-free media containing vehicle (control) or 1 ng/ml TGF-beta 1, in the presence or absence of 100 ng/ml insulin-like growth factor-1 (IGF-I). Under basal conditions, TGF-beta 1 inhibited thymidine incorporation (73.5 +/- 7.3% of control, P < 0.05), but exerted no effect on cellular protein content (97.4 +/- 10.7% of control), an index of hypertrophy. There was no significant alteration of NHE activity, measured as ethylisopropylamiloride (EIPA)-sensitive H+ efflux (2.72 +/- 0.50 vs. control 3.26 +/- 0.68 mmol/liter/min) or 22Na+ influx (2.20 +/- 0.23 vs. control 2.19 +/- 0.19 nmol/mg protein/min). When co-incubated with IGF-I. TGF-beta 1 induced significant PTC hypertrophy (116.9 +/- 8.2% of control, P < 0.05), which was not seen with either agent alone. TGF-beta 1 counteracted the stimulatory effect of IGF-I on DNA synthesis (TGF-beta 1 + IGF-I 103.0 +/- 7.3% vs. IGF-I alone 181.2 +/- 30.3% of control, P < 0.05), but did not affect IGF-I-stimulated EIPA-sensitive 22Na+ influx (3.63 +/- 0.63 vs. IGF-I alone 3.67 +/- 0.50 nmol/mg protein/min, P = NS, both vs. control 2.19 +/- 0.19 nmol/mg protein/min, P < 0.05). Similar results were obtained when NHE activity was measured as EIPA-sensitive H+ efflux. Moreover, the kinetics of NHE activation by the combination of TGF-beta 1 and IGF-I (involving an increase in Vmax) were identical to that previously found for PTC exposed to IGF-I alone. The study demonstrates that TGF-beta 1 elicits distinct PTC growth responses in the presence and absence of IGF-I, without modification of NHE activity. The combination of predominant PTC hypertrophy and enhanced proximal tubule Na+ reabsorption found in many conditions that are associated with renal growth is likely to require the integrated actions of both TGF-beta 1 and IGF-I.
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            Growth hormone, the insulin-like growth factor system, and the kidney


              Author and article information

              Nephron Exp Nephrol
              Cardiorenal Medicine
              S. Karger AG
              December 1999
              28 October 1999
              : 7
              : 5-6
              : 470-478
              aDepartment of Renal Medicine, Princess Alexandra Hospital, Brisbane, and bDepartment of Medicine, University of Sydney at Royal North Shore Hospital, Sydney, Australia
              20626 Exp Nephrol 1999;7:470–478
              © 1999 S. Karger AG, Basel

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              Figures: 6, References: 49, Pages: 9
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