Role of insulin and insulin‐like‐growth factor (IGF) receptors in renal proximal tubule (PT) phosphorus handling

Abstract

The renal PT is involved in the control of phosphorus (P) homeostasis via regulated reabsorption by the sodium phosphate cotransporter (NaPi‐2 or Slc34a1). Previous work suggests NaPi‐2 activity is increased by insulin and/or IGF; however, the mechanisms remain obscure. Our aim was to determine whether PT‐cell‐select knockout (KO) of both the insulin receptor (IR) and the IGF1 receptor (IGFR) would impact NaPi‐2 regulation and phosphorus homeostasis. Mice with both IR and IGF1R genes floxed were crossed for 2 generations with mice with Cre‐recombinase driven by the PT‐select γ‐glutamyl transferase promoter. No differences due to genotype were observed in food intake, body weight, or growth rate in either male (M) or female (F) mice. Similarly, 24‐hour urine volumes and P excretion did not differ. In contrast, plasma P levels were significantly lower in adult KO (6‐9 months) as compared to wild‐type (WT) mice (mg/dl): 12.9 ± 1.2 (WTM), 16.5 ± 2.3 (WTF), 10.2 ± 0.3 (KOM), 8.9 ± 1.3 (KOF), p = 0.014, 2‐way ANOVA for genotype, with no significant effect of sex. Western blotting of whole kidney homogenates revealed no differences due to genotype or sex for the major (84 kDa) band of NaPi‐2; however, a higher molecular weight band on the NaPi‐2 blots (~250 kDa) was markedly reduced in the KO, as well as in female mice. Band densities were (% WTM): 100 ± 7 (WTM), 32 ± 11 (WTF), 16 ± 9 (KOM), 1.6 ± 0.5 (KOF), p <0.001 for genotype and sex. We speculate that this band may represent NaPi‐2 bound to regulatory proteins. Our data support a role for insulin and/or IGF1 receptor‐mediated action in the regulation of renal P reabsorption. Additional studies will be needed to determine the role and cellular actions of each individual receptor.