Consugar, Mark

Background Studies have shown that cilia are mechanical fluid shear sensors. We have reported previously that polycystins, ADPKD proteins, play a role in mechanosensation in mouse kidney epithelial cilia. Objective The current study was designed to analyze the functions of polycystins in human cells. Methods Epithelial cells were isolated from normal and ADPKD (both normal‐looking and dilated/cystic tubules) kidneys. These cells were subject to fluid shear analysis. Results Both immortalized and primary cultured renal tubular cells originating from normal human and non‐dilated ADPKD patient kidneys displayed normal ciliary expressions of the polycystins and responded to fluid flow shear stress with a change in cytosolic calcium. In contrast, immortalized and primary cultured cyst‐lining epithelial cells from ADPKD patients with PKD1 mutation or with abnormal ciliary expression of polycystins were not responsive to fluid shear stress. Conclusion Cyst‐lining epithelia in ADPKD kidneys have lost their ciliary mechanosensing ability. Thus, we propose that loss of mechanosensation in the renal tubular epithelia is a feature of the cyst lining epithelia and monitoring cytosolic calcium in this flow assay is a useful functional readout of polycystin function. This work is supported by the NIH and PKD foundation.

Abstract Fibrous dysplasia (FD) of bone is characterized by focal replacement of normal bone and marrow with abnormal bone and fibrous tissue. It arises from postzygotic activating mutations of the GNAS1 gene. Hypophosphatemia due to renal phosphate wasting has been reported in association with FD as a part of the McCune-Albright Syndrome (MAS), which is characterized by FD, skin hyperpigmentation, and precocious puberty. To date, the prevalence and mechanism of phosphate wasting has not been well studied. We evaluated 42 patients with FD/MAS. Serum and urine samples were tested for indices of mineral metabolism, amino acid handling, and markers of bone metabolism. Twenty (48%) patients had some degree of renal phosphate wasting. Nephrogenous cyclic adenosine monophosphate (cAMP) was normal in FD patients, suggesting that the underlying cause of phosphate wasting is not the presence of activating GNAS1 mutations in the kidney. In addition, there was evidence of a more generalized renal tubulopathy as represented by the presence of abnormal vitamin D metabolism, proteinuria in 36 (86%) patients, and aminoaciduria in 39 (94%) patients. Renal phosphate wasting significantly correlated with the degree of bone involvement, as assessed by serum and urine markers of bone metabolism, suggesting that a circulating factor produced by FD bone and impacting on the kidney may be the mechanism. These data show that phosphaturia as part of a generalized renal tubulopathy represents the most common extraskeletal manifestation of FD and that the observed tubulopathy is similar to that seen in tumor-induced osteomalacia (TIO).