Sunday, April 28, 2024
4/28/2024
PROJECT SUMMARY The global burden of kidney disease is substantial and increasing, with a recent estimated global prevalence of over 700 million cases, with over 37 million in the United States. Mitochondrial dysfunction leading to metabolic dysregulation manifested by suppressed fatty acid oxidation is a key component in the development of kidney disease. Ketone metabolism is a central component of metabolic homeostasis. Ketogenesis occurs when fatty acids are oxidized and converted into ketones. While the liver is the main ketogenic organ, mitochondrial Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), the rate limiting enzyme for ketogenesis, is induced in the proximal tubule of the kidney in response to fasting. Using liver- and kidney-specific Hmgcs2 deletion mouse models, we found that renal HMGCS2 does not contribute to circulating ketones during fasting and is thus likely acting locally. Based on our preliminary data, we hypothesize that proximal tubular HMGCS2 has two independent intra-renal functions. First, we hypothesize that there is regional ketone metabolic cooperativism in the kidney whereby ketones are produced by the proximal tubule and are utilized by the distal convoluted tubule. This is based on our finding that the spatial expression of HMGCS2 in the proximal tubule follows a pattern in which HMGCS2-expressing proximal tubular cells are in close proximity to distal convoluted tubular cells that highly express the ketolytic enzyme 3-Oxoacid CoA-Transferase 1. Second, we hypothesize that there is a cell autonomous effect of proximal tubular HMGCS2. Using a mouse model capable of isolating proximal tubular- specific mitochondria with or without Hmgcs2 deletion, we found that HMGCS2 deficient mitochondria have a mitochondrial respiratory defect. Next, we discovered that after renal ischemia-reperfusion injury (IRI), kidney HMGCS2 is suppressed in both the early injury and late fibrotic phases. This is consistent with human CKD kidney biopsies which also exhibit suppressed HMGCS2 levels. Importantly, we found that mice lacking renal Hmgcs2 are more susceptible to renal IRI, developing more acute tubular damage and late fibrosis, relative to controls. Combining a conditional deletion strategy and capitalizing on our model capable of isolating kidney cell- specific mitochondria, we aim to understand the intra-renal ketone metabolic network in kidney health and disease. In this proposal, we will test the central hypothesis that proximal tubular HMGCS2 acts locally to 1) engage in de novo ketogenesis to fuel neighboring distal convoluted tubular cells, and to 2) support proximal tubular mitochondrial respiration and function. In Aim 1, we will define proximal tubular and distal convoluted tubular ketone metabolism and determine whether the distal convoluted tubule preferentially utilizes proximal tubule-derived ketones for energy. In Aim 2, we dissect the intracellular role of proximal tubular HMGCS2 in supporting mitochondrial function in fasting and ischemic kidney injury.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
