Renal Cellular and Molecular Biology Section

Maurice B Burg, MD, Principal Investigator

	DNA damage exists in mouse inner medullas in vivo under the normal condition of high NaCl and urea. Read more.

Our focus has been on the mechanisms by which cells in the renal medulla withstand the high concentrations of salt (NaCl) and urea that occur there when the kidney produces concentrated urine and that are much higher than elsewhere in the body. We initially identified some organic osmolytes (sorbitol, glycine betaine, glycerophosphocholine (GPC) and myo-inositol) that renal medullary cells accumulate during antidiuresis. Then, we established tissue culture models to elucidate the protective function of the osmolytes and the mechanisms by which they are accumulated (reviewed in Garcia-Perez, et al, 1991 ).

We discovered the biochemical mechanisms by which the organic osmolytes are accumulated. High NaCl increases synthesis of sorbitol from glucose by increasing the amount of the enzyme, aldose reductase, and  increases transport of glycine betaine and myo-inositol into the cells by increasing the number of transporters. The transcription of the aldose reductase and transporter genes is osmotically regulated. We identified an osmotic response element (ORE) in the aldose reductase gene and similar elements have been identified in the transporter genes. Currently, we are studying a transcription factor, TonEBP, whose binding to the ORE and whose transactivating activity are increased by hypertonicity, signaled by protein kinases, including PKA (Ferraris, et al, 2002). 

Our ongoing work also concerns the genomic stress that can occur at extremes of high NaCl or urea and result in cell cycle arrest and apoptosis.  Recent findings are that high NaCl causes DNA damage and impairs DNA repair, not only in cell culture, but also in vivo (Dmitrieva, et al, 2003).  Moreover, the damage is less if the cells are not proliferating rapidly (Zhang, et al, 2002) and if the changes in NaCl and urea concentration are slow (Cai, et al, 2002, 2004), as occurs in the renal inner medulla in vivo.

Publications

Article: Cellular Response to Hyperosmotic Stresses

Hyperosmolality-induced Changes (Excel , 614 kb)

The number of references is arbitrarily limited to 3 or 4.  Entries include all information contained in any of the references.  Gene is the official name for Homo Sapiens.
 
Abbreviations: "Cell": pr = primary culture. "Change": A = activity, B = binding, P = protein abundance, Ph = phosphorylation, R = mRNA abundance, T = transcription, TL = translocation.  "Osmotic increase".  Solute added: Cl = chloride,  G = glucose, M = mannitol, Na = NaCl, NaU = NaCl and urea in combination, N-MG = N-methyl-v-glucamine chloride, R = raffinose, S = sorbitol, Suc = sucrose, T = trehalose, U = urea, Xy = xylose.   "Time":  adptd = adapted, h = hours, m = minutes, s = seconds, steady = long term

Conditions in vivo: AQP1 KO = aquaporin 1 knockout, dehyd = dehydration, furos = furosemide.

Questions, comments and suggestions about this page may be addressed to Maurice Burg