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Life-Long Suppression of Growth Hormone-Insulin-Like Growth Factor I Activity in Genetically Altered Rats Could Prevent Age-Related Renal Damage

Department of Pathology (Y.Z., V.T.L., T.T., M.S.R.), Nagasaki University Graduate School of Biomedical Sciences; and Department of Investigative Pathology (Y.H., I.S.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan

Address all correspondence and requests for reprints to: M. Shawkat Razzaque, M.D., Ph.D., Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. E-mail: sasebo{at}gmail.com.

To determine whether life-long reduction in the GH/IGF-I activity could be renoprotective and attenuate renal damage, we examined the kidneys of transgenic strain of rats whose GH gene was suppressed by an antisense GH transgene. Male rats homozygote for the transgene (tg/tg) had a reduced number of pituitary GH-secreting cells, and 53% less plasma concentration of IGF-I, compared with wild-type (wt/wt) rats at 6 months of age. We compared the kidneys obtained from male wild-type young (6 months) and old (24 months) rats with male homozygote transgenic young (6 months) and old (24 months) rats. The wild-type rats showed features of renal damage as they grew older, including glomerulosclerosis (higher sclerosis index at 24 months; P < 0.0001), tubulointerstitial widening (increased interstitial volume at 24 months; P < 0.0001), and presence of phenotypically altered myofibroblasts and increased accumulation of collagens. Life-long suppression of GH/IGF-I activity resulted in prevention of age-associated renal diseases in homozygote transgenic rats at 24 months (sclerosis index: 1.65 ± 0.11 in wild-type vs. 0.463 ± 0.061 in transgenic rats; interstitial volume: 34.2 ± 0.82 in wild-type vs. 12.8 ± 0.32 in homozygote transgenic rats at 24 months; P < 0.0001). Such reno-protective effects in transgenic rats were associated with decreased renal accumulation of ED-1-positive macrophages, and less renal expression of pro-fibrogenic factors, including connective tissue growth factor and heat shock protein 47. Our in vivo genetic manipulation study provides direct evidence of reno-protective effects of life-long suppression of GH/IGF-I system, by reducing renal infiltration of inflammatory cells, and by suppressing the synthesis of profibrogenic factors and accumulation of extracellular matrix protein.

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