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Kidney cell survival in high tonicity
1Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. JHandler@PHNET.SPH.JHU.EDU
Summary
Mammalian kidney medulla cells accumulate osmolytes like myo-inositol and betaine in hypertonic conditions. This accumulation is regulated by increased gene transcription of specific transporters and enzymes, with a key 12-bp DNA sequence identified.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Physiology
Background:
- Mammalian kidney medulla experiences significant tonicity changes, influencing urine concentration.
- Cells in hypertonic medulla accumulate compatible osmolytes: myo-inositol, betaine, taurine, sorbitol, and glycerophosphorylcholine.
Purpose of the Study:
- To investigate the mechanisms of compatible osmolyte accumulation in kidney cells under hypertonic stress.
- To identify the molecular basis for the transcriptional regulation of osmolyte transporters and enzymes.
Main Methods:
- Utilized kidney-derived cell cultures to study osmolyte accumulation mechanisms.
- Employed cloned cDNAs for cotransporters and aldose reductase to analyze gene expression.
- Investigated gene promoter regions to identify regulatory sequences conferring osmotic responsiveness.
Main Results:
- Hypertonicity increases the activity of sodium-coupled transporters for myo-inositol, betaine, and taurine.
- Sorbitol accumulation is mediated by increased aldose reductase synthesis, converting glucose.
- Glycerophosphorylcholine accumulates due to reduced degradation in hypertonic environments.
- Hypertonicity upregulates transcription of genes for myo-inositol, betaine cotransporters, and aldose reductase.
- A specific 12-bp sequence in the 5' region of the betaine cotransporter gene confers transcriptional response to hypertonicity.
Conclusions:
- Kidney cells employ multiple strategies to manage hypertonicity, including transporter regulation, enzyme synthesis, and degradation inhibition.
- Transcriptional control, mediated by specific DNA sequences, is a key mechanism for adapting to medullary hypertonicity.
- Identified a critical 12-bp sequence in the betaine cotransporter gene promoter responsible for osmotic transcriptional regulation.