Downregulation of NaPi-IIa and NaPi-IIb Na⁺-coupled Phosphate Transporters by Coexpression of Klotho

Abstract

Klotho, a transmembrane protein, protease and hormone has been shown to exert a profound effect on phosphate metabolism. Klotho overexpression lowers and Klotho deficiency increases the plasma phosphate concentration, effects in part attributed to an inhibitory effect of Klotho on the formation of 1,25-dihydroxycholecalciferol (1,25(OH) ₂D₃), the active form of Vitamin D. Beyond that Klotho has been shown to decrease renal tubular phosphate transport more directly. The influence of Klotho on the plasma phosphate concentration contributes to the profound effect of Klotho on ageing and life span. The present study explored whether Klotho influences the major renal tubular (NaPi-IIa) and the major intestinal (NaPi-IIb) phosphate transporters. For functional analysis NaPi-IIa or NaPi-IIb were expressed in Xenopus oocytes both, without or with additional coexpression of Klotho and electrogenic phosphate transport was estimated from the phosphate-induced current (Ip). According to RT-PCR Klotho is expressed in the murine kidney and intestine. Coexpression of Klotho decreased Ip in both NaPi-IIa- and NaPi-IIb-expressing oocytes. Klotho decreased the maximal Ip without appreciably affecting the concentration required for halfmaximal Ip. Treatment of NaPi-IIa- or NaPi-IIb-expressing oocytes with Klotho protein similarly decreased Ip. In conclusion, Klotho down regulates both, renal (NaPi-IIa) and intestinal (NaPi-IIb) phosphate transporters.

Upregulation of the large conductance voltage- and Ca2+-activated K+ channels by Janus kinase 2

“…For generating cRNA (18), the constructs encoding the mouse Ca 2ϩ -insensitive BK channel (BK M513Iϩ⌬899 -903 ) (45, 64) (kindly provided by J. Lingle), wild-type human JAK2, human inactive K882E JAK2 mutant, and human gain-of-function V617F JAK2 mutant (21,22) were used. The constructs were used for generation of cRNA as described previously (9,55). The Ca 2ϩ -insensitive BK mutant was utilized because the activity of wild-type BK requires an increase in the intracellular Ca 2ϩ level in oocytes, which leads to likely side effects interfering with the measurement (11).…”

Molecular and Biochemical Aspects of Hypophosphatemic Rickets; an Updated Review

“…The presence of α-Klotho is crucial for signal transduction of FGF23 through its receptor. 51 2.1.3. FGF23/KLOTHO Complex Mitogen-activated protein kinase (MAPK) is activated by the FGF23-Klotho-FGFR complex.…”

“…Based on recent research, Klotho is capable of impinging on the expression of Napi-2a in an independent manner. 51 …”

Upregulation of KCNQ1/KCNE1 K+channels by Klotho

“…38 The constructs were used for the generation of cRNA as described previously. 58,59 Voltage clamp in Xenopus oocytes Xenopus oocytes were prepared as previously described.…”

“…28,29,[34][35][36] and affects cardiac repolarization. 37 Besides its impact on 1,25(OH) 2 D 3 formation, Klotho may regulate Na + , phosphate cotransport, 38,39 Na + /K + ATPase, 40 Ca 2+ channels, 41 and renal outer medullary K + channels 42 by more direct influence on the channels and transport proteins. The present study thus explored whether Klotho modifies the function of KCNQ1/KCNE1 channels.…”