Localization and function of the renal calcium-sensing receptor

The ability to monitor changes in the ionic composition of the extracellular environment is a crucial feature that has evolved in all living organisms. The cloning and characterization of the extracellular calcium-sensing receptor (CaSR) from the mammalian parathyroid gland in the early 1990s provided the first description of a cellular, ion-sensing mechanism. This finding demonstrated how cells can detect small, physiological variations in free ionized calcium (Ca 2+) in the extracellular fluid and subsequently evoke an appropriate biological response by altering the secretion of parathyroid hormone (PTH) that acts on PTH receptors expressed in target tissues, including the kidney, intestine, and bone. Aberrant Ca 2+ sensing by the parathyroid glands, as a result of altered CaSR expression or function, is associated with impaired divalent cation homeostasis. CaSR activators that mimic the effects of Ca 2+ (calcimimetics) have been designed to treat hyperparathyroidism, and CaSR antagonists (calcilytics) are in development for the treatment of hypercalciuric disorders. The kidney expresses a CaSR that might directly contribute to the regulation of many aspects of renal function in a PTH-independent manner. This Review discusses the roles of the renal CaSR and the potential impact of pharmacological modulation of the CaSR on renal function

What is damaging the kidney in lupus nephritis?

Despite marked improvements in the survival of patients with severe lupus nephritis over the past 50 years, the rate of complete clinical remission after immune suppression therapy i

Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations

Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood

Hereditary tubular transport disorders: implications for renal handling of Ca2+ and Mg2+.

Contains fulltext : 88379.pdf (publisher's version ) (Open Access)The kidney plays an important role in maintaining the systemic Ca2+ and Mg2+ balance. Thus the renal reabsorptive capacity of these cations can be amended to adapt to disturbances in plasma Ca2+ and Mg2+ concentrations. The reabsorption of Ca2+ and Mg2+ is driven by transport of other electrolytes, sometimes through selective channels and often supported by hormonal stimuli. It is, therefore, not surprising that monogenic disorders affecting such renal processes may impose a shift in, or even completely blunt, the reabsorptive capacity of these divalent cations within the kidney. Accordingly, in Dent's disease, a disorder with defective proximal tubular transport, hypercalciuria is frequently observed. Dysfunctional thick ascending limb transport in Bartter's syndrome, familial hypomagnesaemia with hypercalciuria and nephrocalcinosis, and diseases associated with Ca2+-sensing receptor defects, markedly change tubular transport of Ca2+ and Mg2+. In the distal convolutions, several proteins involved in Mg2+ transport have been identified [TRPM6 (transient receptor potential melastatin 6), proEGF (pro-epidermal growth factor) and FXYD2 (Na+/K+-ATPase gamma-subunit)]. In addition, conditions such as Gitelman's syndrome, distal renal tubular acidosis and pseudohypoaldosteronism type II, as well as a mitochondrial defect associated with hypomagnesaemia, all change the renal handling of divalent cations. These hereditary disorders have, in many cases, substantially increased our understanding of the complex transport processes in the kidney and their contribution to the regulation of overall Ca2+ and Mg2+ balance.1 januari 201

Physiology of the distal convolution:convergence of electrolyte transport pathways.

Contains fulltext : 82951.pdf (publisher's version ) (Open Access)Radboud Universiteit Nijmegen, 4 november 2010Promotores : Bindels, R.J.M., Hoenderop, J.G.J. Co-promotor : Deinum, J.256 p

Renal compensation to chronic hypoxic hypercapnia: downregulation of pendrin and adaptation of the proximal tubule.

Contains fulltext : 51556.pdf (publisher's version ) (Open Access)The molecular basis for the renal compensation to respiratory acidosis and specifically the role of pendrin in this condition are unclear. Therefore, we studied the adaptation of the proximal tubule and the collecting duct to respiratory acidosis. Male Wistar-Hannover rats were exposed to either hypercapnia and hypoxia [8% CO(2) and 13% O(2) (hypercapnic, n = 6) or normal air (controls, n = 6)] in an environmental chamber for 10 days and were killed under the same atmosphere. In hypercapnic rats, arterial pH was lower than controls (7.31 +/- 0.01 vs. 7.39 +/- 0.01, P = 0.03), blood HCO(3)(-) concentration was increased (42 +/- 0.9 vs. 32 +/- 0.24 mM, P < 0.001), arterial Pco(2) was increased (10.76 +/- 0.4 vs. 7.20 +/- 0.4 kPa, P < 0.001), and plasma chloride concentration was decreased (92.2 +/- 0.7 vs. 97.2 +/- 0.5 mM, P < 0.001). Plasma aldosterone levels were unchanged. In the proximal tubule, immunoblotting showed an increased expression of sodium/bicarbonate exchanger protein (188 +/- 22 vs. 100 +/- 11%, P = 0.005), confirmed by immunohistochemistry. Total Na/H exchanger protein expression in the cortex was unchanged by immunoblotting (119 +/- 10 vs. 100 +/- 11%, P = 0.27) and immunohistochemistry. In the cortex, the abundance of pendrin was decreased (51 +/- 9 vs. 100 +/- 7%, P = 0.003) by immunoblotting. Immunohistochemistry revealed that this decrease was clear in both cortical collecting ducts (CCDs) and connecting tubules (CNTs). This demonstrates that pendrin expression can be regulated in acidotic animals with no changes in aldosterone levels and no external chloride load. This reduction of pendrin expression may help in redirecting the CNT and CCD toward chloride excretion and bicarbonate reabsorption, contributing to the increased plasma bicarbonate and decreased plasma chloride of chronic respiratory acidosis

Acute and chronic effects of growth hormone on renal regulation of electrolyte and water homeostasis.

Contains fulltext : 52219.pdf (publisher's version ) (Closed access)For decades, growth hormone (GH) has been known to influence electrolyte and water handling in humans and animals. However, the molecular mechanisms underlying the GH-induced anti-natriuretic and anti-diuretic effects have remained elusive. This review will examine the existing literature on renal electrolyte and water handling following acute and chronic GH-exposure. Renal responses to GH differ in acute and chronic models. Acute application of GH results in a reduced urinary electrolyte and water excretion, whereas the chronic effects of GH are more diverse, as this state likely represents a complex mixture of primary and secondary actions of GH as well as compensatory mechanisms. During chronic GH-exposure an initial sodium retaining state often occurs, followed by a normalization of the urinary sodium excretion, although extracellular volume expansion still persists. We recently described a possible mechanism by which GH acutely increases renal electrolyte and water reabsorption, by modulation of the kidney specific Na(+), K(+), 2Cl(-) co-transporter (NKCC2). The primary aim of this review is to investigate how GH-induced regulation of NKCC2 may be involved in the complex renal changes previously described during acute and chronic GH. We propose, that the GH-induced increase in NKCC2 activity may explain the initial water and sodium retention seen in a number of studies. Moreover, renal changes seen during prolonged GH-exposure may now be seen on the background of the acute stimulation of NKCC2. Additionally, GH also promotes renal acidification, thus influencing renal acid/base handling. The GH-induced renal acidification is partly compatible with changes in NKCC2 activity. Finally, we review the available data on changes in hormonal systems affecting tubular transport during acute and chronic GH-exposure

A single simple procedure for dewaxing, hydration and heat-induced epitope retrieval (HIER) for immunohistochemistry in formalin fixed paraffin-embedded tissue

<p>Heat-induced epitope retrieval (HIER) is widely used for immunohistochemistry on formalin fixed paraffin-embedded tissue and includes temperatures well above the melting point of paraffin. We therefore tested whether traditional xylene-based removal of paraffin is required on sections from paraffin-embedded tissue, when HIER is performed by vigorous boiling in 10 mM Tris/0.5 mM EGTA-buffer (pH=9). Immunohistochemical results using HIER with or without prior dewaxing in xylene were evaluated using 7 primary antibodies targeting proteins located in the cytosol, intracellular vesicles and plasma membrane. No effect of omitting prior dewaxing was observed on staining pattern. Semiquantitative analysis did not show HIER to influence the intensity of labelling consistently. Consequently, quantification of immune labelling intensity using fluorescent secondary antibodies was performed at 5 dilutions of primary antibody with and without prior dewaxing in xylene. No effect of omitting prior dewaxing on signal intensity was detectable indicating similar immunoreactivity in dewaxed and non-dewaxed sections. The intensity of staining the nucleus with the DNA-stain ToPro3 was similarly unaffected by omission of dewaxing in xylene. In conclusion, the HIER procedure described and tested can be used as a single procedure enabling dewaxing, hydration and epitope retrieval for immunohistochemistry in formalin fixed paraffin-embedded tissue.</p