The parathyroid hormone-vitamin D 3 endocrine system, as well as dietary phosphorus, plays an important role in regulating renal and gastrointestinal absorption of phosphate. Recently, emerging evidence suggests that other systemic and/or paracrine/autocrine factors are present in bones for maintaining phosphate homeostasis, such as fibroblast growth factor-23 (FGF-23), 1 frizzled-related protein-4 (FRP-4), and matrix extracellular phosphoglycoprotein (MEPE) (1-11). These three factors were highly expressed in tumors isolated from oncogenic osteomalacia patients and reduced phosphate transport in kidney. Among these factors, FGF-23 strongly suppressed 1␣,25(OH) 2 D 3 production and elicited hypophosphatemia. Administration of the recombinant FGF-23 protein reduced serum phosphorus without affecting serum calcium, as well as increasing renal phosphorus excretion in mice (12). Mice bearing FGF-23-expressing Chinese hamster ovary cells showed suppressed 25-hydroxyvitamin D 3 1␣-hydroxylase mRNA expression in the kidney (3). FGF-23 mRNA is expressed in a variety of tissues such as thymus, brain, bone, thyroid/parathyroid gland, and heart (2, 3, 13). Recent studies (13, 14) indicated FGF-23 mRNA as well as FGF-23 protein was elevated in bones from patients with McCune-Albright syndrome and also in bones from HYP mouse, mouse homologue to X-linked hypophosphatemic (XLH) rickets. However, the level of serum FGF-23 in hypophosphatemic patients with XLH is still controversial (15-17). Hyperphosphatemic patients with chronic kidney disease showed significant elevation in circulating FGF-23, which correlated with serum phosphorus and creatinine (16, 18 -20), suggesting (a) serum phosphorus was a possible regulator of FGF-23 production or (b) circulating FGF-23 accumulated in chronic renal failure.The purpose of this study was to evaluate the effects of dietary phosphorus and 1␣,25(OH) 2 D 3 on FGF-23 production. Administration of FGF-23 protein or overexpression of Fgf23 gene in rodent suppressed 1␣,25(OH) 2 D 3 production by reducing 25-hydroxyvitamin D 3 1␣-hydroxylase in the proximal tubules (12, 21-23). On the contrary, Fgf23-null mice reported increased circulating 1␣,25(OH) 2 D 3 despite hyperphosphatemia, hypercalcemia, and low PTH levels (24). Administration of 1␣,25(OH) 2 D 3 increased serum FGF-23 in normal mice (25). These observations suggested mutual regulation between FGF-23 and 1␣,25(OH) 2 D 3 ; however, 1␣,25(OH) 2 D 3 administration also increases intestinal phosphate uptake and suppresses PTH. Thus, we used thyroparathyroidectomized rats as well as 5/6 nephrectomized rats fed a diet with various kinds of phosphorus content to examine the direct effect of 1␣,25(OH) 2 D 3 administration on serum FGF-23.* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.§ To whom correspondence should be addressed. Tel.: 81-550-87-6735; Fax: 81-550-8...

Cobalt achieved renal protection independently of metabolic status and blood pressure. Its effect was attributed to the upregulation of HIF and HIF-regulated genes and to a mitigated advanced glycation and oxidative stress.

Hyperinsulinemia has been implicated in the development of diabetic nephropathy. In the present study we compared the renoprotective effects of the thiazolidinedione, pioglitazone (PGZ), to that of insulin in a hypertensive, obese, type II diabetic rat model. PGZ aggravated obesity and gave less glycemic control than insulin. However, renoprotection was markedly better with PZG compared to insulin as shown by lower proteinuria, improved renal function, and less histological evidence of diabetic glomerular and tubulointerstitial lesions. PZG and insulin both reduced renal accumulation of pentosidine and oxidative stress to a similar extent. In contrast, PGZ but not insulin suppressed enhanced transforming growth factor-beta (TGF-beta) expression. We further confirmed in cultured rat proximal tubular cells that insulin enhanced TGF-beta mRNA expression and protein production. Our results identify hyperinsulinemia and the attendant increase of TGF-beta expression as potential therapeutic targets in diabetes independent of glycemic control. This confirms prior clinical evidence that PZG provides renoprotection in obese, diabetic patients with nephropathy.

An inorganic phosphate (Pi)-restricted diet is important for patients with chronic kidney disease and patients on hemodialysis. Phosphate binders are essential for preventing hyperphosphatemia and ectopic calcification. The sodium-dependent Pi (Na/Pi) transport system is involved in intestinal Pi absorption and is regulated by several factors. The type II sodium-dependent Pi transporter Npt2b is expressed in the brush-border membrane in intestinal epithelial cells and transports Pi. In the present study, we analyzed the phenotype of Npt2b−/− and hetero+/− mice. Npt2b−/− mice died in utero soon after implantation, indicating that Npt2b is essential for early embryonic development. At 4 wk of age, Npt2b+/− mice showed hypophosphatemia and low urinary Pi excretion. Plasma fibroblast growth factor 23 levels were significantly decreased and 1,25(OH)2D3 levels were significantly increased in Npt2b+/− mice compared with Npt2b+/+ mice. Npt2b mRNA levels were reduced to 50% that in Npt2b+/+ mice. In contrast, renal Npt2a and Npt2c transporter protein levels were significantly increased in Npt2b+/− mice. At 20 wk of age, Npt2b+/− mice showed hypophosphaturia and reduced Na/Pi cotransport activity in the distal intestine. Npt2b+/+ mice with adenine-induced renal failure had hyperphosphatemia and high plasma creatinine levels. Npt2b+/− mice treated with adenine had significantly reduced plasma Pi levels compared with Npt2b+/+ mice. Intestinal Npt2b protein and Na+/Pi transport activity levels were significantly lower in Npt2b+/− mice than in the Npt2b+/+ mice. The findings of the present studies suggest that Npt2b is an important target for the prevention of hyperphosphatemia.

These findings indicate that abnormal Pi metabolism may also be involved in tight junction molecules such as Cldns that are affected by Npt2b deficiency.