established that serum phosphate levels decreased in FGF23 knockout mice following FDA approved drug high throughput screening exogenous FGF23 administration, but not in klotho knockout mice identifying the obligate role of klotho.[16] The site of klotho expression in the nephron and actions related to signal transduction relationships remain controversial. While FGF23 has been found to bind to multiple FGFR,[84] signalling by FGF23 was seen only with FGFR-1c, 3c and -4 in cell lines that co-express klotho.[15] In rats, members of the FGFR family are expressed in the kidney at specific locations. FGFR-3 is
expressed in both proximal and distal tubules whilst FGFR-1 and-4 are only seen in distal tubules.[85] In vitro studies support FGFR-3 as the physiologically relevant receptor in FGF23 downstream signalling because phosphate transport occurs in the proximal tubules. Interestingly, a study by Liu et al. concluded that FGFR-3 and FGFR-4 did not mediate renal effects of FGF23 and instead, FGFR-1 was seen to co-localize with klotho in mice in the
distal tubules.[85] While this study suggests distal tubule distribution, more recent studies have reported convincing proximal tubular distribution, which is more physiologically likely since this is where most phosphate transport occurs.[7, 21, 22, 76] Nevertheless, a distal selleck compound tubule response manifests itself early either directly or indirectly via proximal tubule signalling,[86] and exact human mechanisms are yet to be validated. Andrukhova et al. have established that FGF23 directly acts in a murine proximal tubule cell culture model to downregulate NaPi-IIa through extracellular signal-regulated kinases (ERK)-1/2 and serum/glucocorticoid-regulated kinase-1 (SGK1) signalling and this pathway is dependent on the presence of klotho at physiological FGF23 levels.[22] Through its enzymatic
activity, sKl can act directly to reduce recycling of NaPi-IIa, thereby itself inducing Palmatine a phosphaturic response.[76] It is plausible that while mKl is abundant within the distal tubules, proximal tubule distribution of mKl facilitates some degree of phosphate excretion and cleaved sKl through paracrine action promotes a response in the proximal tubule despite being cleaved downstream. These exact mechanisms are still unclear. One of the earliest abnormalities that develops as kidney function declines is a sustained reduction in tubular phosphate reabsorption resulting from the phosphaturic actions of FGF23 and PTH.[2, 87] As the remaining nephrons attempt to preserve phosphate balance, the amount of phosphate excreted per nephron increases, with increases in single-nephron glomerular filtration and fractional excretion of phosphate (FEPi) measurements.[87, 88] Ultimately serum phosphate levels are affected when the declining kidney is no longer able to compensate for the reduction in total phosphate excretion.[88] This is usually observed when the glomerular filtration rate (GFR) falls below 30 mL/min.
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