Vertebrates constantly remodel bone to maintain a constant bone mass. Bone remodeling comprises two phases: bone resorption by the osteoclasts followed by bone formation by the osteoblasts. Although the prevailing view about the control of bone remodeling is that it is an autocrine/paracrine phenomenon, the bone resorption arm of bone remodeling is under a tight endocrine control. To date little is known about the regulation of bone formation. We took the observations that gonadal failure favors bone loss and obesity protects from it as an indication that bone mass, body weight, and reproduction could be regulated by the same hormone(s). Leptin is one of these hormones. Leptin inhibits bone formation by the osteoblasts. This function is dominant, and leptin deficiency results in a high bone mass phenotype despite the hypogonadism characterizing these animals. Genetic biochemical and physiological studies demonstrate that leptin inhibits bone formation following its binding to its receptor in the hypothalamus. These results are the first evience that bone remodeling is a hypothalamic process; they imply necessarily that osteoporosis, the most frequent bone remodeling disease, is partly at least a hypothalamic disease. This finding also has therapeutic implications.
These data demonstrate that regression of biopsy-proven glomerulosclerosis can be achieved in various experimental settings. The potential importance of the RAS in renal fibrosis is underscored by the effectiveness of therapies that aim to inhibit its manifold actions, including induction of PAI-1. An understanding of the interactions of the RAS with the immune response, aldosterone, and PAI-1, as well as the dynamic control of cell proliferation, apoptosis, and regeneration, is now evolving. Ongoing studies will establish which of these recent provocative findings from animal models are relevant to human diseases, and may lead to optimal therapies to fore-stall progression and perhaps even induce regression of sclerosis.
In a brief period, we have accrued a new view of Ang II. From conventional signaling pathways, our attention was directed toward signal transduction involving specific tyrosine kinases, inducing not only vasocontriction but also proto-oncogene expression, protein synthesis, hypertrophy and growth. More recently, our attention has been directed beyond these effects to inflammatory reactions involving NF-kappa B activation and related gene expression. The mechanisms are not known for certain but probably initially involve the generation of ROS. The subsequent NF-kappa B activation probably involves participation of endothelin signaling and, perhaps, NF-AT3 activation. It is possible that other compounds can also modulate Ang II-induced inflammatory responses.
Chronic renal failure and arterial hypertension run in parallel. New goal BP levels have been established as 130/85 mm Hg and 125/75 mm Hg, depending on whether the level of proteinuria is less than or greater than 1 g/d. New and lower threshold BP (> 130/85 mm Hg) to initiate pharmacologic therapy is required in the presence of renal failure, to facilitate the strict BP control that is required. Hence, it is necessary to consider that both renal and cardiovascular protection are obtained with strict BP control, which otherwise seems to require blockade of angiotensin II effects when proteinuria above 1 g/d is present.
