Mice have become the most commonly used animal species for studies of experimental acute kidney injury (AKI) and acute renal failure (ARF). This preference stems from a variety of factors, including relative cost, the heterogeneity of available strains, the availability of protean molecular probes for studying this species, and their utility for induction of specific genetic alterations, such as whole animal- or tissue specific- gene knock-outs. For a variety of reasons, most studies are performed when the mice are within the first 4 months of life. However, our laboratory has recently observed that during this early maturation period, which corresponds with rapid growth (e.g., a 3x increase in body weight), there is a profound change in renal susceptibility to diverse forms of attack. Thus, whereas 1 month old mice are almost completely resistant to at least three ARF models, 4 month old mice subjected to the same injury protocols sustain severe tubular necrosis, cast formation, and filtration failure. The goal of the proposed work is to better characterize, and to gain initial insights into, how this change from an """"""""injury resistant"""""""" to an """"""""injury sensitive"""""""" phenotype occurs. This work is deemed to be important for the following reasons: 1) it may have potentially profound implications for the conduct, and interpretation of, future studies of AKI;2) new insights into critical determinants of cellular injury, in general, could result;and 3) understanding why 1 month old mice have profound resistance to tubular injury could potentially lead to new therapeutic insights. Towards these ends, four Specific Aims are proposed:
Specific Aim 1 will further characterize determinants of this maturation - AKI susceptibility effect at the whole animal level (further definition of age, sex, and strain effects on AKI susceptibility and recovery rates). Whether this age dependent switch in injury susceptibility is renal specific, or whether it is also expressed in extra-renal tissues, will be determined.
Specific Aim 2 will assess potential biochemical pathways through which this changing cell phenotype occurs (primary alterations in cellular energetics, oxidant stress, phospholipid hydrolysis, inflammation, apoptosis). If the maturation process has a dominant impact on a specific injury- inducing pathway, subsequent studies will be designed to address underlying molecular mechanisms.
Specific Aims 3 and 4 will further characterize why two critical cytoprotective pathways, HMG CoA reductase (Aim 3), and heme oxygenase-1 (Aim 4), are in flux during the early maturation process, and whether these changes impact renal susceptibility to AKI / ARF. These experiments have been designed to generate (Aims 1 &2), and preliminarily test (Aim 3 &4), new hypotheses for future study. Hence, a two year study (R-21) is proposed to gain initial insights that will help focus more in depth future investigation.
As animals, and presumably humans, grow and develop, their kidneys become progressively more sensitive to injury. The goal of this application is to determine why this occurs, because this will yield new insights into mechanisms of disease. The ultimate goal is to develop pharmacologic strategies that can protect high risk patients from the onset of severe, acute kidney injury and its adverse sequelae that frequently result in death.
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|Zager, Richard A; Johnson, Ali C M (2010) Progressive histone alterations and proinflammatory gene activation: consequences of heme protein/iron-mediated proximal tubule injury. Am J Physiol Renal Physiol 298:F827-37|