Insulin-Like Growth Factor-I Ameliorates Delayed Kidney Graft Function and the Acute Nephrotoxic Effects of Cyclosporine1

Maestri, Marcello; Dafoe, Donald C.; Adams, Gregg A.; Gaspari, A; Luzzana, F; Innocente, Francesco; Rademacher, Johannes; Dionigi, Paolo; Barbieri, Annalisa; Zonta, F; Zonta, A.; Rabkin, Ralph

doi:10.1097/00007890-199707270-00001

Cited by 14 publications

(7 citation statements)

References 16 publications

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“…It has been demonstrated in several reports that IGF-1 prevents apoptotic cell death in neuronal cells (3,10,26,35), as well as in cardiac fibroblasts (28). In the kidney, IGF-1 was found to accelarate recovery in renal failure (18) and to improve the acute nephrotoxic effects of cyclosporine (24). Since our results show so far that AmB does not cause significant apoptosis in mesangial cells and since mesangial cells are known to be the only cells of the kidney to produce IGF-1 intrinsically (2, 9, 34), we hypothesize that IGF-1 might elicit a protective effect in toxic renal injury.…”

Section: Resultsmentioning

confidence: 98%

Apoptosis Contributes to Amphotericin B- Induced Nephrotoxicity

Varlam

Siddiq

Parton

et al. 2001

Antimicrob Agents Chemother

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The aim of this study was to investigate whether apoptosis contributes to nephrotoxicity caused by amphotericin B (AmB). By detecting apoptosis-specific DNA fragmentation, it is demonstrated that proximal tubular cells (LLC-PK 1 ) and medullary interstitial cells (RMIC) respond with programmed cell death when treated with therapeutic doses of AmB. Concomitant application of AmB and recombinant human insulin-like growth factor-1 (rhIGF-1), a known antiapoptotic agent, abrogated apoptosis in vitro. To validate that the observed apoptotic effects on renal tissue culture cells are applicable to an in vivo setting, an animal model was used for verification. Therefore, Sprague-Dawley rats were treated with AmB. The drug caused hypokalemia, decreased weight gain, loss of renal concentrating ability, and dehydration in a dose-dependent fashion. Microscopic examination of renal tissue sections revealed apoptotic alterations predominantly in proximal and distal tubular epithelial cells. To verify that the observed clinical side effects were linked to apoptosis, rhIGF-1 was applied concomitantly with AmB. In all animals, rhIGF-1 prevented the above-mentioned clinical side effects. Moreover, significantly reduced apoptosis was observed in renal tissue sections of these animals, indicating the relevance of apoptosis in nephrotoxicity. This is the first report to demonstrate that AmB induces apoptosis in the rat kidney in a dose-dependent fashion. The incidence of apoptosis correlates with renal toxicity and can be abrogated by concomitant treatment with rhIGF-1.

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Section: Resultsmentioning

confidence: 98%

Apoptosis Contributes to Amphotericin B- Induced Nephrotoxicity

Varlam

Siddiq

Parton

et al. 2001

Antimicrob Agents Chemother

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“…This study clearly showed that trophic factors influenced cold ischemic injury by interaction with the tissue during cold storage and not merely by being present during rewarming and reperfusion. Some of the factors used here, such as IGF‐1 and EGF, have the potential to exert beneficial effects by affecting mechanisms of reperfusion injury (16–18). However, we have shown that these potential effects on reperfusion did not play a role in the improved kidney function obtained with trophic factors when used, as in this study, only in the storage solution.…”

Section: Discussionmentioning

confidence: 99%

“…IGF‐1 is protective against renal injury. It can accelerate recovery from ischemia when administered either at the time of injury, after 24 h or if given prior to injury (18, 63). IGF‐1 likely decreases during storage due to a specific IGF‐1 degrading system in kidney membranes (64), which may render the graft more susceptible to cold ischemic injury.…”

Section: Discussionmentioning

confidence: 99%

Successful Six‐Day Kidney Preservation Using Trophic Factor Supplemented Media and Simple Cold Storage

McAnulty

Reid

Waller

et al. 2002

American Journal of Transplantation

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This study examined the effect of trophic factor supplementation [TFS; bovine neutrophil peptide-1 (bactenecin), 1 mg/L; substance P, 2.5 mg/L; nerve growth factor, 20 mg/L; epidermal growth factor, 10 mg/L; insulin-like growth factor-1, 10 mg/L] during cold storage with UW lactobionate solution. Dogs transplanted with kidneys stored for 4 days in TFS-UW had significantly lower peak serum creatinine values (mean 2.9 ∫ 0.2 mg/dL) and returned to normal values faster (6 days) than kidneys stored for 3 days in unmodified UW solution (4.2 ∫ 0.3 mg/dL and 14 days, respectively). Kidneys stored for 5 days in TFS-UW (mean peak creatinine 3.7 ∫ 0.3) functioned equivalently to kidneys stored for 3 days and better than kidneys stored for 4 days in UW alone. Dogs with kidneys stored for 6 days in TFS-UW had mean peak creatinines of 5.7 ∫ 0.4 mg/dL. These returned to normal creatinine values in 14 days, equal to 3-day stored and significantly better than kidneys stored for 4 days in UW alone (20 days recovery time). This study shows trophic factor deprivation appears to be a critical mechanism of injury in organ preservation with current synthetic storage media, and marks the initial development of a synthetic biologically active preservation solution, the next generation of preservation media.

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“…Recently Chao et al (43) demonstrated that local insulinlike growth factor-I gene transfer, which constitutively activates Akt but does not increase serum insulin-like growth factor-I, thus avoiding increased inflammatory reactions, protects cardiomyocytes from ischemia/reperfusion. Some have demonstrated that insulin-like growth factor-I treatment ameliorates ischemic acute renal failure (44,45), whereas others have reported that insulin-like growth factor-1 worsens kidney I/R injury because of greater inflammatory responses (46,47).…”

Section: Gender Differences On Renal Function and Morphology Aftermentioning

confidence: 99%

Testosterone Is Responsible for Enhanced Susceptibility of Males to Ischemic Renal Injury

Park

Kim

Ahn

et al. 2004

Journal of Biological Chemistry

303

273

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Female mice are much more resistant to ischemia/ reperfusion (I/R)-induced kidney injury when compared with males. Although estrogen administration can partially reduce kidney injury associated with I/R, we demonstrated that the presence of testosterone, more than the absence of estrogen, plays a critical role in gender differences in susceptibility of the kidney to ischemic injury. Testosterone administration to females increases kidney susceptibility to ischemia. Dihydrotestosterone, which can not be aromatized to estrogen, has effects equal to those of testosterone. Castration reduces the I/R-induced kidney injury. In contrast, ovariectomy does not affect kidney injury induced by ischemia in females. Testosterone reduces ischemia-induced activation of nitric oxide synthases (NOSs) and Akt and the ratio of extracellular signal related kinase (ERK) to c-jun N-terminal kinase (JNK) phosphorylation. Pharmacological (N -nitro-L-arginine) or genetic (endothelial NOS or inducible NOS) inhibition of NOSs in females enhances kidney susceptibility to ischemia. Nitric oxide increases Akt phosphorylation and protects MadinDarby canine kidney epithelial cells from oxidant stress. Antagonists of androgen or estrogen receptors do not affect the gender differences. In conclusion, testosterone inhibits the post-ischemic activation of NOSs and Akt and the ratio of ERK to JNK phosphorylation through non-androgen receptor-medicated mechanisms, leading to increased inflammation and increased functional injury to the kidney. These findings provide a new paradigm for the design of therapies for ischemia/ reperfusion injury and may be important to our understanding of the pathophysiology of acute renal failure in pregnancy where plasma androgen levels are elevated.

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Insulin-Like Growth Factor-I Ameliorates Delayed Kidney Graft Function and the Acute Nephrotoxic Effects of Cyclosporine1

Abstract: In evaluating this study it should be recognized that the animal models studied, although widely used, differ from the human condition. However, IGF-I and des(1-3)IGF-I exhibit properties that strongly suggest their value in preventing clinical DGF, and they deserve further studies.

Cited by 14 publications

References 16 publications

Apoptosis Contributes to Amphotericin B- Induced Nephrotoxicity

Apoptosis Contributes to Amphotericin B- Induced Nephrotoxicity

Successful Six‐Day Kidney Preservation Using Trophic Factor Supplemented Media and Simple Cold Storage

Testosterone Is Responsible for Enhanced Susceptibility of Males to Ischemic Renal Injury

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