IN-DEPTH REVIEW Effects of Excess PTH on Nonclassical Target Organs Susanne Bro, MD, PhD, and Klaus Oigaard, MD 0 The classical target organs for parathyroid hormone (PTH) are the bone and kidneys. In uremia, however, numerous studies have shown that PTH may also affect the function of a number of nonclassical organs and tissues besides the bone and kidney, including the brain, heart, smooth muscles, lungs, erythrocytes, lymphocytes, pancreas, adrenal glands, and testes. Most of these effects do not apply to the generally accepted actions or normal regulatory mecha- nisms of PTH. Thus, the potential role of PTH as one of the possibly many toxins in uremia is of current interest. The molecular basis for the actions of elevated PTH levels on various nonrenal and nonskeletal organs or tissues might be mediated via the widespread distribution of the classical PTlUPTH-related peptide (PTHrP) receptors and via tha novel PTH2 receptors. The present survey deals with an evaluation of the nonrenal and nonskeletal effects of excess PTH in uremia, taking into consideration the presently available information on the organ-specific expression of the classical and novel PTH receptors, and of the expression and function of PTHrP. 0 1997 by the National Kidney Foundation, Inc. INDEX WORDS: PTH; PTHrP; PTH/PTHrP receptors; PTHP receptors; intracellular calcium; nervous system; pitu- itary gland; adrenal cortex; beta islets of the pancreas; testes; cardiovascular system; arterial hypertension; skeletal muscles; immune system; hematopoietic system; lungs; lipid metabolism; skin. T HE CLASSICAL target organs for parathy- roid hormone (PTH) are the bone and kid- neys. In uremia, however, numerous studies have shown that PTH may also affect the function of a number of nonclassical organs and tissues besides the bone and kidney, including the brain, heart, smooth muscles, lungs, erythrocytes, lym- phocytes, pancreas, adrenal glands, and testes.’ These observations have emerged from studies conducted in humans and laboratory animals with chronic renal failure (CRF) and marked ele- vations of plasma PTH. In 1977, Massry2 sug- gested the hypothesis that PTH might be one of the uremic toxins. Since there was no obvious physiologic link between calcium homeostasis and the function of many of these organs, the mechanism behind the responses of these non- classical target organs to PTH was poorly under- stood at that time. The cloning in 1987 of the PTH-related pep- tide (PTHrP) by Suva et al3 and the cloning in 1991 of the common receptor for PTH and From the Nephrological Department P, Rigshospitalet, University of Copenhagen, Denmark. Received January 16, 1997; accepted in revisedform June 13, 1997. Address reprint requests to Susanne Bro, MD, PhD, Nephrological Department P 2132, Rigshospitalet, 9 Bleg- damsvej, DK-2100 Copenhagen, Denmark. E-mail: bcc3515@vip.cybercityy.dk 0 1997 by the National Kidney Foundation, Inc. 0272~6386/97/3005-0003$3.00/O PTHrP by Jiippner et aL4 however, have provided a molecular basis for an understanding of some of these effects of PTH on organs, which were not considered to be classical targets for the ac- tion of PTH. PTHrP is produced by virtually all tissue types in the body, but is present at very low circulating concentrations in normal conditions. PTHrP is thought to act mainly in an autocrine/ paracrine mode,5 it binds with the same affinity as PTH to the classical PTH receptors, and it induces a similar activating response of the sec- ondary messengers.4 Messenger RNA for the classical PTH receptor is particularly abundant in kidney and bone, but is in fact expressed in a wide variety of normal tissues.6,7 Since supra- physiologic concentrations of PTH in general are required to induce functional responses in non- classical tissues, it is possible that PTHrP rather than PTH might be the natural ligand for the classical PTH receptors in most of these non- PTH classical target tissues. Furthermore, the wide distribution of the re- cently discovered PTH2 receptor, which binds PTH but not PTHrP,839 indicates that action via these receptors may contribute to the PTH effects in a number of organ systems besides the kidney and bone. The present survey deals with an evaluation of the nomenal and nonskeletal effects of excess PTH in uremia, taking into consideration the presently available information on the organ-spe- cific expression of the classical and novel PTH 606 American Journal of Kidney Diseases, Vol 30, No 5 (November), 1997: pp 606-620