Inhibition Of Renal Injury

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

Acute kidney injury (previously known as acute renal failure) has a high morbidity and mortality. After developing a novel model of sepsis-induced AKI that employs cecal ligation puncture (CLP) in elderly mice treated with fluids and antibiotics, we are using the model to study the pathophysiology of injury, to screen drugs, and to study their mechanisms of action, including conscious blood pressure by telemetry. We adjusted our mouse model by using outbred mice, which develop AKI at a younger age, and we established another model using comorbidity, namely pre-existing renal dysfunction, which is thought to increase susceptibility to AKI in patients. This acute-on-chronic syndrome has not been studied in animals, and the nephrology field is trying to gain more information about how this is manifest in patients. Because the model we used for pre-existing renal dysfunction (folic acid) is reversible, unlike the progression seen in CKD patients, we started with a partial renal ablation (5/6 nephrectomy) procedure, a classic rat CKD model, then adapted it to the mouse. We have characterized our model, and it has several hallmarks of progressive CKD, including hypertension, proteinuria, glomerulosclerosis, interstitial renal tubular fibrosis, anemia, and cardiac fibrosis. In order to make our CKD mouse model compatible with our sepsis AKI models, we tested three mouse strains, which had differential susceptibility to CKD. In the most susceptible strain, all aspects of CKD could be lowered by an angiotensin receptor blocker (olmesartan). Conversely, angiotensin II could convert a resistant strain to a susceptible strain. However, this effect is largely independent of blood pressure. Because the folic acid model is highly variable, we are developing an additional model using a different nephrotoxin to induce CKD. 1) We are continuing our collaboration with Tom Eggerman, where we used CD36 KO, SR-BI/II KO and double knockout to protect against sepsis and sepsis-AKI. We are developing a cellular approach to therapy. 2) We are developing a new mouse diabetes model using the Akita mutation in a different background strain. We are testing how these mice differ from normal mice after CLP-induced sepsis-AKI. 3) We are developing a new method to (primary) culture mouse kidney proximal tubule cells that preserves their morphology and epithelial functions. We are testing the polarity of processes including the release of mitochondrial DNA in response to pathophysiologic stimuli. 4) We are developing a mouse model for progressive chronic kidney that does not require 5/6 nephrectomy surgery. We continue to explore potential mechanisms and treatments for sepsis-AKI, CKD, and acute-on-chronic kidney disease. We also continue to develop models for acute and chronic kidney disease.