Acute kidney injury (AKI) is a devastating disease with a high mortality rate. Apoptosis and necrosis play major roles in AKI, but there is a fundamental knowledge gap of the factors regulating their induction in AKI. Continued existence of this gap represents a significant problem as AKI has a high mortality rate and there are very few therapeutic interventions to alter the clinical course of this disease. The long-term goal is t uncover mechanisms involved in AKI for the development of novel therapeutics to protect the kidney. Ceramides regulate apoptosis and necrosis and are elevated in the kidney in several models of AKI. The factors that regulate production of ceramides during kidney apoptosis and necrosis and whether ceramides lead to apoptotic versus necrotic kidney cell death are completely unknown. Likewise, there are many different ceramide species and the roles for particular ceramide species in AKI have not been determined. This proposal will answer these questions to achieve the objective of developing ceramides as novel therapeutic approaches for the treatment of AKI. Preliminary data demonstrate that: (i) long-chain ceramides (C16 - C20- ceramides) are generated via de novo synthesis during kidney cell apoptosis and blocking their generation inhibits apoptosis; (ii) the pro-apoptotic BCL-2 protein BAK is a key regulator of ceramide synthases (CerS) and long-chain ceramide generation during kidney cell apoptosis; (iii) acid sphingomyelinase (aSMase) generated very long-chain ceramides (C24-C26-ceramides) occurs in kidney cell necrosis; (iv) kidney cortical CerS and acid SMase are activated and specific ceramides elevated several-fold in in vivo rodent models of AKI (cisplain nephrotoxicity and rhabdomyolysis-induced AKI); and (v) mice given inhibitors of enzymes responsible for ceramide synthesis are protected from cisplatin-induced AKI. This expanding and developing body of work has led us to propose the following hypothesis: nephrotoxic stimuli elevate specific species of kidney ceramides through CerS and SMase-mediated pathways, inducing kidney cell death and ultimately kidney failure. This hypothesis will be tested with three specific aims: (1) determine the mechanism by which BAK regulates CerS activity and generation of specific long-chain ceramides during kidney cell apoptosis; (2) determine the contribution of SMase-generated ceramide to kidney cell necrosis; and (3) determine the in vivo contribution of CerS and aSMase to cisplatin-induced AKI in mice. The approach is innovative because it will identify the mechanism by which BAK regulates ceramide synthases as well as the specific role of individual ceramide species in vivo in AKI. The proposed research is significant as it advances our current knowledge of mechanisms of kidney cell death AKI. Ultimately such knowledge has the potential to greatly improve the treatment of AKI.

Public Health Relevance

This proposal will advance current knowledge of mechanisms of acute kidney injury by identifying factors that regulate generation of specific ceramide species during kidney apoptosis and necrosis. The proposed research is relevant to public health because acute kidney injury has a high mortality rate with very few therapeutic interventions. Thus, information gained from the enclosed studies has the potential to improve the treatment of acute kidney injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093462-06
Application #
9058073
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2012-09-17
Project End
2017-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Louisville
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40208
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Sundararaj, Kamala; Rodgers, Jessalyn I; Marimuthu, Subathra et al. (2018) Neuraminidase activity mediates IL-6 production by activated lupus-prone mesangial cells. Am J Physiol Renal Physiol 314:F630-F642
Sharp, Cierra N; Siskind, Leah J (2017) Developing better mouse models to study cisplatin-induced kidney injury. Am J Physiol Renal Physiol 313:F835-F841
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Dupre, Tess V; Doll, Mark A; Shah, Parag P et al. (2016) Suramin protects from cisplatin-induced acute kidney injury. Am J Physiol Renal Physiol 310:F248-58
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Sharp, Cierra N; Doll, Mark A; Dupre, Tess V et al. (2016) Repeated administration of low-dose cisplatin in mice induces fibrosis. Am J Physiol Renal Physiol 310:F560-8
Skrypnyk, Nataliya I; Siskind, Leah J; Faubel, Sarah et al. (2016) Bridging translation for acute kidney injury with better preclinical modeling of human disease. Am J Physiol Renal Physiol 310:F972-84

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