Search

Brown Norway rats (BN, BN/NHsdMcwi) are profoundly resistant to developing acute kidney injury (AKI) following ischemia reperfusion. To help define the genetic basis for this resistance, we used consomic rats, in which individual chromosomes from BN rats were placed into the genetic background of Dahl SS rats (SS, SS/JrHsdMcwi) to determine which chromosomes contain alleles contributing to protection from AKI. The parental strains had dramatically different sensitivity to ischemia reperfusion with plasma creatinine levels following 45 min of ischemia and 24 h reperfusion of 4.1 and 1.3 mg/dl in SS and BN, respectively. No consomic strain showed protection similar to the parental BN strain. Nine consomic strains (SS-7(BN), SS-X(BN), SS-8(BN), SS-4(BN), SS-15(BN), SS-3(BN), SS-10(BN), SS-6(BN), and SS-5(BN)) showed partial protection (plasma creatinine about 2.5-3.0 mg/dl), suggesting that multiple alleles contribute to the severity of AKI. In silico analysis was performed using disease ontology database terms and renal function quantitative trait loci from the Rat Genome Database on the BN chromosomes giving partial protection from AKI. This tactic identified at least 36 candidate genes, with several previously linked to the pathophysiology of AKI. Thus, natural variants of these alleles or yet-to-be identified alleles on these chromosomes provide protection against AKI. These alleles may be potential modulators of AKI in susceptible patient populations.

Resistance to ischemic acute renal failure in the Brown Norway rat: A new model to study cytoprotection. Background An in vivo model of intrinsic resistance to ischemia could be invaluable to define how specific pathways to injury or putative protectors from injury affect the severity of acute renal failure (ARF). The purpose of this study was to determine whether separate rat strains had differential sensitivity to renal ischemia, characterize the extent of protection, and begin to define differences in gene expression that might impact on the severity of ARF. Methods The sensitivity to 45 minutes of renal ischemia in Sprague-Dawley rat (SD) was compared with 2 lines of Brown-Norway rats (BN/Mcw, BN/Hsd). Constitutive and inducible stress protein expression was compared between strains. Results At 24hours' reperfusion, SD rats had higher creatinine (3.4mg/dL), elevated Na and water excretion, and proximal tubule necrosis. Both strains of BN rats were resistant to loss of renal function (Scr = 0.9mg/dL at 24hours' reflow) and had preserved renal morphology. BN rats had no redistribution of Na,K-ATPase into detergent-soluble cortical extracts found early (15 minutes) after ischemia in SD rats. Hsc73 expression did not differ between strains and was not induced by ischemia. Compared with SD, induction of Hsp25 and 72 by renal ischemia was blunted in both BN strains. Constitutive Hsp25 was higher in both BN-Mcw and BN-Hsd compared with SD rat kidney. Constitutive Hsp72 was significantly higher only in BN-Mcw kidneys. Immunohistochemistry showed baseline Hsp72 and 25 expression was increased in proximal tubules of BN-Mcw versus SD. Conclusion BN rat kidney is resistant to ischemic injury and provides a new model for studying cytoprotective mechanisms. Initial study of strain-specific gene expression suggests particular stress proteins are among the potential mechanisms contributing to protection against ARF.

Acute kidney dysfunction after ischemia-reperfusion injury may be a consequence of persistent intrarenal vasoconstriction. Regulators of G protein Signaling (RGS) proteins are GTPase activating proteins for heterotrimeric G proteins that can regulate vascular tone. RGS4 is expressed in vascular smooth muscle cells in the kidney. However, RGS4 protein levels are low in many tissues as a consequence of N-end rule-mediated polyubiquination and proteasomal degradation. In this work, the role of RGS4 in the renal response to ischemia/reperfusion injury (IRI) was investigated. A murine model of IRI was employed and RGS4-null mice (R4KO) were highly sensitized to the development of renal dysfunction after IRI. Furthermore, R4KO mice exhibited reduced renal blood flow after IRI. Kidneys were studied for intrinsic RGS4 function by ex vivo isolation. R4KO kidneys exhibited increased renal vasoconstriction in response to endothelin-1 infusion. The intrinsic renal activity of RGS4 was examined in an in vivo model of syngeneic renal transplantation. Transplanted R4KO kidneys exhibited significantly reduced reperfusion blood flow and increased renal cell death. To increase RGS4 activity, wild type mice were administered the proteasomal inhibitor MG-132 and this resulted in increased renal RGS4 protein. Furthermore, MG-132 treatment inhibited the development of renal dysfunction after IRI in wild type - but not R4KO - mice. These results demonstrate that RGS4 antagonizes the development of renal dysfunction in response to IRI.

Recent evidence suggests that injury to the renal vasculature may play an important role in the pathogenesis of both early and chronic ischemic acute kidney injury (AKI). Established and new data support the suggestion that vascular injury, in particular, endothelial cell injury, participates in the extent and maintenance of AKI by pathways that are related to vascular tone. Early alterations in peritubular capillary blood flow during reperfusion has been documented and associated with loss of normal endothelial cell function, which can be replaced pharmacologically or with cell replacement interventions. Distorted peritubular capillary morphology is associated with loss of barrier function that may contribute to early alterations in vascular stasis. In addition, ischemia induces alterations in endothelial cells that may promote inflammation and procoagulant activity, thus contributing to vascular congestion. Reductions in microvasculature density may play a critical part in the progression of chronic kidney disease following initial recovery from ischemia/reperfusion-induced AKI. The exact nature of how capillary loss alters renal function and predisposes renal disease is thought to be due at least in part to hypoxia. Finally, the loss of endothelial cell function may represent an important therapeutic target in which nitric oxide, vascular trophic support, and/or endothelial progenitor cells may show potential importance in ameliorating the acute and/or chronic effects of ischemic AKI.

Transcriptome analysis and kidney research: Toward systems biology. An enormous amount of data has been generated in kidney research using transcriptome analysis techniques. In this review article, we first describe briefly the principles and major characteristics of several of these techniques. We then summarize the progress in kidney research that has been made by using transcriptome analysis, emphasizing the experience gained and the lessons learned. Several technical issues regarding DNA microarray are highlighted because of the rapidly increased use of this technology. It appears clear from this brief survey that transcriptome analysis is an effective and important tool for question-driven exploratory science. To further enhance the power of this and other high throughput, as well as conventional approaches, in future studies of the kidney, we propose a multidimensional systems biology paradigm that integrates investigation at multiple levels of biologic regulation toward the goal of achieving a global understanding of physiology and pathophysiology.

Acute kidney injury following folate administration is characterized by a vascular remodeling that is initially proliferative but subsequently results in vascular endothelial loss. Interventions directed toward promoting endothelial growth may preserve vascular structure and therefore renal function. However, angiopoietin-1 therapy in the setting of folate-induced acute kidney injury resulted in an expanded fibrotic response despite apparent preservation of the vasculature, indicating that renal repair responses are complex and vascular-directed therapies should be approached with caution.