Stanniocalcin-1 secretion and receptor regulation in kidney cells

Abstract

Kidney collecting duct principal cells are the main source of stanniocalcin-1 (STC-1) production and secretion. From there, the hormone targets thick ascending limb and distal convoluted tubule cells, as well as collecting duct cells. More specifically, STC-1 targets their mitochondria to exert putative antiapoptotic effects. Two distal tubule cell lines serve as models of STC-1 production and/or mechanism of action. Madin-Darby canine kidney-1 (MDCK-1) cells mimic collecting duct cells in their synthesis of STC-1 ligand and receptor, whereas inner medullary collecting duct-3 (IMCD-3) cells respond to additions of STC-1 by increasing their respiration rate. In the present study, MDCK cell STC-1 secretion was examined under normal and hypertonic conditions, vectorally, and in response to hormones and signal transduction pathway activators/inhibitors. STC-1 receptor regulation was monitored in both cell lines in response to changing ligand concentration. The results showed that NaCl-induced hypertonicity had concentration-dependent stimulatory effects on STC-1 secretion, as did the PKC activator TPA. Calcium and ionomycin were inhibitory, whereas calcium receptor agonists had no effect. Angiotensin II, aldosterone, atrial natriuretic factor, antidiuretic hormone, and forskolin also had no effects. Moreover, STC-1 secretion exhibited no vectoral preference. STC-1 receptors were insensitive to homologous downregulation in both cell lines. In contrast, they were upregulated when STC-1 secretion was inhibited by calcium. The findings suggest that hypertonicity-induced STC-1 secretion is regulated through PKC activation and that high intracellular calcium levels are a potent inhibitor of release. More intriguingly, the results suggest that the receptor may not accompany STC-1 in its passage to the mitochondria.

The mitochondrial component of intracrine action

“…In renal tubular cells, more than 90% of cell-associated STC is associated with mitochondria. Collectively, these findings demonstrate that STC is an intracrine which trafficks to mitochondria and to a lesser extent to the nucleus (60,65,66,77).…”

“…Stanniocalcin 1 (STC) is a secreted signaling protein that stimulates phosphate reabsorption in the renal tubules (65,66,77). It is synthesized in a variety of tissues including bone, prostate, renal tubules, ovary, and thyroid among others.…”

“…STC appears to upregulate uncoupling protein 2 in macrophages and uncoupling protein 3 in cardiomyocytes, and there is evidence to indicate that STC does lead to uncoupling of the mitochondrial respiratory chain. In macrophages this uncoupling leads to less efficient ATP formation and a reduction in the generation of ROS (2,16,65,66,77). It will be recalled that uncoupling protein 1 is found in brown fat and is responsible for nonshivering thermogenesis.…”

Stanniocalcin-1 in the subfornical organ inhibits the dipsogenic response to angiotensin II

“…Therefore, STC-1 may be involved in maintaining the integrity of SFO neurons by functioning as an antiapoptotic agent, as suggested for cortical neurons (70), kidney collecting ducts (9), and cardiomyocytes (30). Furthermore, Sazonova et al (49) have reported that STC-1 receptors within the kidney are not downregulated in the presence of elevated STC-1, indicating that these cells continue to regulate cytosolic calcium levels despite chronic stimuli that would further induce elevated intracellular calcium. Such a cellular mechanism would be of considerable importance in SFO, as it is not only constantly exposed to changes in circulating ANG II, but must be able to respond appropriately to activate neuronal systems to restore body fluid and electrolyte balance.…”

Toxicological impacts of a botanical pesticide, azadirachtin on corpuscles of Stannius of stinging catfish, Heteropneustes fossilis

“…Ishibashi and Imai (2002) have suggested that STC homologs may also be present in tetrapods. Although no homologous structure of CS has been localized in higher vertebrates, immunocytochemically stanniocalcin (STC 1 and STC 2) has been identified in the kidney, ovary, pancreas (alpha cells) and bladder of human and rat (Ishibashi and Imai 2002;Song et al 2006;Sazonova et al 2008;Trindade et al 2009). Recently, Roch and Sherwood (2010) have cloned three stanniocalcins from two invertebrates, the tunicate Ciona intestinalis and the amphioxus Branchiostoma floridae.…”