Rapid downregulation of rat renal Na/P(i) cotransporter in response to parathyroid hormone involves microtubule rearrangement

J Clin Invest. 1999 Aug;104(4):483-94. doi: 10.1172/JCI3208.

Abstract

Renal proximal tubule cells express in their apical brush border membrane (BBM) a Na/P(i) cotransporter type IIa that is rapidly downregulated in response to parathyroid hormone (PTH). We used the rat renal Na/P(i) cotransporter type IIa (NaPi-2) as an in vivo model to assess early cellular events in the rapid downregulation of this transporter. When rats were treated with PTH for 15 minutes, NaPi-2 abundance in the BBM was decreased. In parallel, transporter accumulated in intracellular vesicles. Concomitantly, microtubules (MTs) were found to form dense bundles of apical-to-basal orientation. After 60 minutes of PTH action, the cells were vastly depleted of NaPi-2, whereas their microtubular cytoskeleton had returned to its normal appearance. Prevention of MT rearrangement by taxol resulted in accumulation of NaPi-2 in the subapical cell portion after 15 minutes and a strong delay in depletion of intracellular transporter after 60 minutes of PTH action. Furthermore, the subapical accumulation of NaPi-2 was associated with the expansion of dense apical tubules of the subapical endocytic apparatus (SEA). Depolymerization of MTs by colchicine likewise caused a retardation of intracellular NaPi-2 depletion. These results suggest that NaPi-2 is downregulated in response to PTH through a rapid endocytic process in 2 separate steps: (a) internalization of the transporter into the SEA, and (b) its delivery to degradative organelles by a trafficking mechanism whose efficiency depends on a taxol-sensitive rearrangement of MTs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / metabolism*
  • Colchicine / pharmacology
  • Endocytosis / drug effects
  • Immunohistochemistry
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / ultrastructure
  • Male
  • Microscopy, Electron
  • Microtubules / drug effects*
  • Microvilli / drug effects
  • Microvilli / metabolism
  • Paclitaxel / pharmacology
  • Parathyroid Hormone / pharmacology*
  • Peptide Fragments / pharmacology*
  • Phosphates / metabolism
  • Rats
  • Rats, Wistar
  • Sodium / metabolism
  • Sodium-Phosphate Cotransporter Proteins
  • Sodium-Phosphate Cotransporter Proteins, Type IIa
  • Symporters*

Substances

  • Carrier Proteins
  • Parathyroid Hormone
  • Peptide Fragments
  • Phosphates
  • Slc34a1 protein, rat
  • Sodium-Phosphate Cotransporter Proteins
  • Sodium-Phosphate Cotransporter Proteins, Type IIa
  • Symporters
  • Sodium
  • Paclitaxel
  • Colchicine