Submitted on July 18, 2007
Accepted on November 21, 2007
Genome-wide gene expression profiling reveals renal genes regulated during metabolic acidosis
Marta Nowik1, M. Rita Lecca2, Ana Velic3, Hubert Rehrauer4, Andre W Brandli2, and Carsten A Wagner1*
1 Institute of Physiology, University of Zurich, Zurich, Switzerland
2 Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Federal Institute of Technology, ETH Zurich, Zurich, Switzerland
3 Institute of Physiology, University of Zurich, Switzerland
4 Functional Genomics Center Zurich, University of Zurich, Zurich, Switzerland
* To whom correspondence should be addressed. E-mail: wagnerca{at}access.unizh.ch.
Production and excretion of acids are balanced to maintain systemic acid-base homeostasis. During metabolic acidosis (MA) excess acid accumulates and is removed from the body, a process achieved, at least in part, by increasing renal acid excretion. This acid-secretory process requires the concerted regulation of metabolic and transport pathways, which are only partially understood. Chronic MA causes also morphological remodelling of the kidney. Therefore, we characterized transcriptional changes in mammalian kidney during MA to gain insights into adaptive pathways. Total kidney RNA from control, 2 and 7 days NH4Cl treated mice was subjected to microarray gene profiling. We identified 4075 transcripts significantly (p <0.05) regulated after 2 and / or 7 days of treatment. Microarray results were confirmed by qRT-PCR. Analysis of candidate genes revealed that a large group of regulated transcripts was represented by different solute carrier transporters, genes involved in cell growth, proliferation, apoptosis, water homeostasis, and ammoniagenesis. Pathway analysis revealed that oxidative phosphorylation was the most affected pathway. Interestingly, the majority of acutely regulated genes after 2 days, returned to normal values after 7 days suggesting that adaptation had occurred. Besides these temporal changes, we detected also differential regulation of selected genes (SNAT3, PEPCK, PDG) between early and late proximal tubule. In conclusion, the mammalian kidney responds to MA by temporally and spatially altering the expression of a large number of genes. Our analysis suggests that many of these genes may participate in various processes leading to adaptation and restoration of normal systemic acid-base and electrolyte homeostasis.
