The kidney has contributed two critical insights to an understanding of the mechanism by which all mammalian cells sense oxygen. The first followed from the detailed characterization of the regulation of expression of erythropoietin by oxygen and led to the discovery of the hypoxically regulated transcription factor, HIF (hypoxia-inducible factor). The second insight developed from the exploration of the molecular pathogenesis of von Hippel Lindau disease protein whose mutation is characterized by the development of renal cancers. The essential role for the von Hippel Lindau disease protein in the oxygen-dependent degradation of HIF led directly to the discovery of the oxygen sensing mechanism that regulates HIF by oxygen-dependent peptidyl hydroxylation. This understanding now generates novel therapeutic possibilities and is providing insights into the mechanisms of other renal diseases.

Therapeutic attempts with anti-fibrotic drugs are still at an experimental stage. The clinical efficacies of most agents listed in Table II have not been proved. Some potential agents, such as colchicine, analogues of PGE, gamma-interferon, inhibitors of prolyl hydroxylase, malotilate, and PUL, must be further evaluated in controlled clinical trials. In addition, almost all anti-fibrotic agents, except HOE 077, are neither liver-nor fibrosis-specific. Some site-directed (targeted) drug delivery systems, drug-loaded vesicle carrier systems, like liposomes and erythrocyte ghosts, which selectively affect the extracellular matrix-producing cells, may improve efficacy and reduce adverse effects if they can be carriers for anti-fibrotic agents. Developments in biochemistry, immunohistochemistry, and molecular biology have considerably advanced our understanding of pathogenic mechanisms of hepatic fibrosis. With the development of available pathologic and serologic markers for ongoing fibrogenesis, experimental and clinical anti-fibrotic trials have become more active. Some therapeutic strategies have chosen targets for interference in collagen metabolism. In vivo inhibition of Ito cell activation has been a focus for the anti-fibrotic studies (70). In the present review an update of pharmacologic intervention in the process of metabolic pathways of collagen, the main extracellular matrices in both interstitium and basement membrane, has been summarized. Several drugs or biochemical agents that act on different steps of collagen synthesis, crosslinking, and breakdown are listed and discussed briefly. Moreover, agents that inhibit other matrix components are also involved in the review.(ABSTRACT TRUNCATED AT 250 WORDS)

L-ascorbic acid is an essential cofactor for lysyl hydroxylase and prolyl hydroxylase, enzymes essential for collagen biosynthesis. In addition, L-ascorbic acid preferentially stimulates collagen synthesis in a manner which appears unrelated to the effect of L-ascorbic acid on hydroxylation reactions. This reaction is stereospecific and unrelated to intracellular degradation of collagen. The effect apparently occurs at a transcriptional or translational level, since L-ascorbic acid preferentially stimulates collagen-specific mRNA. In addition, it stimulates lysyl hydroxylase activity but inhibits prolyl hydroxylase activity in human skin fibroblasts in culture.

For almost 40 years, diphenylhydantoin has been the preferred drug in the treatment of seizure disorders. Soon after the drug was introduced into clinical practice, gingival enlargement was noticed as a side effect and, despite much research effort, the etiology of this condition remains unknown. More recently, diphenylhydantoin-induced osteomalacia and the teratogenic effects of the drug have been reported. Recent advances in our knowledge of these conditions will be discussed and future directions for research will be outlined.

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