Acute Kidney Injury
is an acute loss of kidney function common in hospitalized patients. In fact, nearly 50% of patients in the intensive care unit will suffer from AKI. This loss of kidney function can be somewhat reversible, but in many there are long-term sequelae including a greater predisposition to future AKI events or the development of irreversible or progressive kidney disease. AKI is primarily a disease of the renal tubular epithelia and the interstitium and can be caused by ischemia or nephrotoxin exposure.
Currently there is no accepted treatment outside of supportive care for AKI. We have studied the impact of the Keap1/Nrf2 pathway on AKI-to-CKD development. Nrf2 is a transcription factor that upregulates antioxidant and detoxifying mechanisms in the kidney. Keap1 is the endogenous inhibitor of Nrf2 that prevents its nuclear translocation. Using mice that express low levels of Keap1 we showed that even with the same AKI severity, we can prevent the development of CKD. This suggests that the Nrf2 pathway could be a potent target to improve outcomes after AKI.
One pathological mechanism for AKI is the loss of the small micro-vessels of the kidney also known as microvascular rarefaction. This would predispose the kidney to further hypoxic injury and to progressive tubular atrophy and fibrosis. One of the obstacles to studying this in humans is the lack of a safe, noninvasive method to assess rarefaction in real-time. In collaboration with Dr. Kang Kim in the Vascular Medicine Institute, we have performed studies assessing microvascular rarefaction in a mouse model of AKI due to ischemia-reperfusion using super-resolution ultrasound (SRU). SRU utilizes B-mode ultrasound with super-fast framerate imaging and vascular enhancement with microbubbles such as Definity (perfluten lipid microspheres) which is already FDA-approved for left ventricular opacification in echocardiography. SRU undergoes significant post-imaging processing to isolate the microbubble signals while suppressing surrounding tissue signals (eigen deconvolution), adjusting for motion (respiratory) artifact, to generate a composite image in which vascularity can be quantified. We are now enrolling patients with CKD to translate this technology to the clinic.
Mutchler SM, Hasan M, Kohan DE, Kleyman TR, Tan RJ. Deletion of the gamma subunit of ENaC in endothelial cells does not protect against renal ischemia reperfusion injury (2021). Int J Mol Sci 22(20): 10914. doi: 10.3390/ijms222010914.
Tan RJ, Chartoumpekis DV, Rush BM, Zhou D, Fu H, Kensler TW, Liu Y (2016). Keap1 hypomorphism protects against ischemic and obstructive kidney disease. Sci Rep 2; 6:36185. doi: 10.1038/srep36185
Chen Q, Yu J, Rush BM, Stocker SD, Tan RJ, Kim K (2020). Noninvasive assessment of renal microvasculature changes in mouse acute kidney injury using ultrasound super-resolution imaging. Kidney International. https://doi.org/10.1016/j.kint.2020.02.011
Chronic Kidney Disease
CKD is the permanent loss of kidney function or presence of kidney dysfunction. CKD can lead to end-stage renal disease (ESRD) and the need for dialysis or transplantation for survival. ESRD in the US costs nearly 40 billion USD per year, which is roughly equivalent to the entire budget of the NIH. Our lab has recently focused on proteinuric CKD, generally due to defects in kidney glomeruli, which are responsible for the normal filtration of plasma. This leads to the abnormal leakage of protein into the urine (proteinuria) and is associated with more rapid progression to ESRD. Proteinuria is most commonly caused by diabetes but can also be a result of diseases such as focal segmental glomerulosclerosis, Alport Syndrome, minimal change disease, and membranous nephropathy. As in AKI, we are in great need of better treatments for proteinuric CKD.
As described above, our lab has investigated the role of the Keap1/Nrf2 pathway in kidney disease. While we find that Nrf2 activity is protective in AKI, we have found a paradoxical effect in glomerular diseases to promote podocyte injury. We found that mice with genetic Nrf2 activation develop more severe proteinuria in response to adriamycin, angiotensin II, and BSA overload. We found similar results with a Nrf2 activator related to bardoxolone methyl, CDDO-Im. Nrf2 activity was associated with podocyte foot process effacement, and a reduction in nephrin levels. We are continuing to investigate how Nrf2 directly damages podocytes.
In other studies of proteinuric CKD, we demonstrated that the antioxidant enzyme extracellular superoxide dismutase protects against glomerular injury. This protection was specific for proteinuric CKD, since EC-SOD did not protect against unilateral ureteral obstruction (UUO) injury. In collaboration with Dr. Youhua Liu, we found that the Wnt/beta-catenin system upregulates tubular expression of MMP-7. This MMP-7 then cleaves nephrin on podocytes to promote proteinuria. This tubular-to-glomerular crosstalk is a novel pathway of progression of proteinuric CKD. We have also published a method to isolate intact glomeruli from kidneys for ex vivo cultures.
Rush BM, Bondi CD, Stocker SD, Jobbagy S, Barry KM, Small SM, Stolz DB, Chartoumpekis DV, Kensler TW, and Tan RJ (in press). Genetic or pharmacologic activation of Nrf2 signaling enhances proteinuric chronic kidney disease in mice (2021). Kidney International. 99(1): 102-116. https://doi.org/10.1016/j.kint.2020.07.036
Rush BM, Small SA, Stolz DB, and Tan RJ (2018). An efficient sieving method to isolate intact glomeruli from adult rat kidney. J Vis Exp. (141), e58162, doi: 10.3791/58162
Tan RJ, Zhou D, Xiao L, Zhou L, Li Y, Bastacky SI, Oury TD, Liu Y (2015). Extracellular superoxide dismutase protects against proteinuric kidney disease. J Am Soc Neph. 26(10): 2447-59. https://doi.org/10.1681/asn.2014060613