Calcium (Ca(2+)) and phosphate (P(i)) are essential to many vital physiological processes. Consequently the maintenance of Ca(2+) and P(i) homeostasis is essential to a healthy existence. This occurs through the concerted action of intestinal, renal, and skeletal regulatory mechanisms. Ca(2+) and P(i) handling by these organs is under tight hormonal control. Disturbances in their homeostasis have been linked to pathophysiological disorders including chronic renal insufficiency, kidney stone formation, and bone abnormalities. Importantly, the kidneys fine-tune the amount of Ca(2+) and P(i) retained in the body by altering their (re)absorption from the glomerular filtrate. The ion transport proteins involved in this process have been studied extensively. Recently, new key players have been identified in the regulation of the Ca(2+) and P(i) balance. Novel regulatory mechanisms and their implications were introduced for the antiaging hormone klotho and fibroblast growth factor member 23 (FGF23). Importantly, transgenic mouse models, exhibiting disturbances in Ca(2+) and P(i) balance, have been of great value in the elucidation of klotho and FGF23 functioning. This review highlights the current knowledge and ongoing research into Ca(2+) and P(i) homeostasis, emphasizing findings from several relevant knockout mouse models.

Chronic metabolic acidosis results in renal Ca²⁺ and Mg²⁺ wasting, whereas chronic metabolic alkalosis is known to exert the reverse effects. It was hypothesized that these adaptations are mediated at least in part by the renal Ca²⁺ and Mg²⁺ transport proteins. The aim of this study, therefore, was to determine the effect of systemic acid-base status on renal expression of the epithelial Ca²⁺ channel TRPV5, the Ca²⁺-binding protein calbindin-D_28K, and the epithelial Mg²⁺ channel TRPM6 in relation to Ca²⁺ and Mg²⁺ excretion. Chronic metabolic acidosis that was induced by NH₄Cl loading or administration of the carbonic anhydrase inhibitor acetazolamide for 6 d enhanced calciuresis accompanied by decreased renal TRPV5 and calbindin-D_28K mRNA and protein abundance in wild-type mice. In contrast, metabolic acidosis did not affect Ca²⁺ excretion in TRPV5 knockout (TRPV5^−/−) mice, in which active Ca²⁺ reabsorption is effectively abolished. This demonstrates that downregulation of renal Ca²⁺ transport proteins is responsible for the hypercalciuria. Conversely, chronic metabolic alkalosis that was induced by NaHCO₃ administration for 6 d increased the expression of Ca²⁺ transport proteins accompanied by diminished urine Ca²⁺ excretion in wild-type mice. However, this Ca²⁺-sparing action persisted in TRPV5^−/− mice, suggesting that additional mechanisms apart from upregulation of active Ca²⁺ transport contribute to the hypocalciuria. Furthermore, chronic metabolic acidosis decreased renal TRPM6 expression, increased Mg²⁺ excretion, and decreased serum Mg²⁺ concentration, whereas chronic metabolic alkalosis resulted in the exact opposite effects. In conclusion, these data suggest that regulation of Ca²⁺ and Mg²⁺ transport proteins contributes importantly to the effects of acid-base status on renal divalent handling.

Hypercalciuria increases the risk for urolithiasis, but renal adaptive mechanisms reduce this risk. For example, transient receptor potential vanilloid 5 knockout (TPRV5^−/−) mice lack kidney stones despite urinary calcium (Ca²⁺) wasting and hyperphosphaturia, perhaps as a result of their significant polyuria and urinary acidification. Here, we investigated the mechanisms linking hypercalciuria with these adaptive mechanisms. Exposure of dissected mouse outer medullary collecting ducts to high (5.0 mM) extracellular Ca²⁺ stimulated H⁺-ATPase activity. In TRPV5^−/− mice, activation of the renal Ca²⁺-sensing receptor promoted H⁺-ATPase–mediated H⁺ excretion and downregulation of aquaporin 2, leading to urinary acidification and polyuria, respectively. Gene ablation of the collecting duct-specific B1 subunit of H⁺-ATPase in TRPV5^−/− mice abolished the enhanced urinary acidification, which resulted in severe tubular precipitations of Ca²⁺-phosphate in the renal medulla. In conclusion, activation of Ca²⁺-sensing receptor by increased luminal Ca²⁺ leads to urinary acidification and polyuria. These beneficial adaptations facilitate the excretion of large amounts of soluble Ca²⁺, which is crucial to prevent the formation of kidney stones.

Integrins are transmembrane αβ glycoproteins that connect the extracellular matrix to the cytoskeleton. The laminin-binding integrin α3β1 is expressed at high levels in lung epithelium and in kidney podocytes. In podocytes, α3β1 associates with the tetraspanin CD151 to maintain a functional filtration barrier. Here, we report on a patient homozygous for a novel missense mutation in the human ITGA3 gene, causing fatal interstitial lung disease and congenital nephrotic syndrome. The mutation caused an alanine-to-serine substitution in the integrin α3 subunit, thereby introducing an N-glycosylation motif at amino acid position 349. We expressed this mutant form of ITGA3 in murine podocytes and found that hyperglycosylation of the α3 precursor prevented its heterodimerization with β1, whereas CD151 association with the α3 subunit occurred normally. Consequently, the β1 precursor accumulated in the ER, and the mutant α3 precursor was degraded by the ubiquitin-proteasome system. Thus, these findings uncover a gain-of-glycosylation mutation in ITGA3 that prevents the biosynthesis of functional α3β1, causing a fatal multiorgan disorder.