Adaptive response of the murine collecting duct to alkali loading

Abstract

Fine-tuning of salt and acid-base homeostasis is achieved in the renal collecting duct through the action of intercalated and principal cells. Their activity is tightly regulated adapting to changes in systemic acid-base, fluid, or electrolyte status. The relative number of acid or bicarbonate secretory intercalated cells changes in response to acid or alkali loading. Several factors that may induce collecting duct plasticity in response to acid loading have been identified including cell proliferation, Growth Differentiation Factor 15 (Gdf15), hensin (DMBT1), and SDF1 (or CXCL12). Also, the transcription factors Foxi1 and CP2L1, or the Notch2-Jag1 signaling pathway, may play a role. However, little is known about the mechanisms mediating the adaptive response of the collecting duct to alkali loading. Here, we examined in mouse kidney the response of these factors to alkali loading. Mice were left untreated or received NaHCO3 or NaCl over 7 days. Cell proliferation in vivo was monitored by Ki67 labeling or BrdU incorporation and expression of cell markers, and regulatory factors were examined. Foxi1 and GDF15 were upregulated and CP2L1 downregulated during alkali loading. Ki67 staining and BrdU incorporation were frequent in AQP2-positive cells in the NaCl and NaHCO3 groups, but no evidence was found for increased Ki67 or BrdU staining in bicarbonate-secretory cells consistent with a model that AQP2 positive precursor cells may differentiate into intercalated cells. Thus, alkali loading alters the cellular profile of the collecting duct, which may involve cell proliferation and changes in the network of molecules determining the plasticity of the collecting duct.

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Acknowledgments

The use of the ZIRP Rodent facility is gratefully acknowledged.

Funding

The study was supported by grants from the Swiss National Science Foundation (31003A, 155959, and 176125) to C. A. Wagner.

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A.G., N.M., A.D., C.B., and C.A.W. performed experiments and analyzed data. A.G., N.M., and C.A.W. wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Carsten A. Wagner.

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Genini, A., Mohebbi, N., Daryadel, A. et al. Adaptive response of the murine collecting duct to alkali loading. Pflugers Arch - Eur J Physiol (2020). https://doi.org/10.1007/s00424-020-02423-z

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Keywords

  • Alkalosis
  • Kidney
  • Collecting duct
  • Pendrin
  • Remodeling
  • Intercalated cell differentiation