Mechanisms of Mitochondrial Metabolic Dysfunction in Chronic Kidney Disease

Ut Southwestern Medical Center, Dallas TX

Investigators

Abstract

PROJECT SUMMARY Chronic kidney disease (CKD) is a growing global health problem with a recent estimated global prevalence of over 700 million cases, with over 37 million in the United States. Even after clinical recovery from one episode of acute kidney injury (AKI), patients who survive AKI after hospital discharge have an 8.8-fold increased risk of developing CKD and a 3.3-fold increased risk for developing end stage renal disease. Mitochondrial dysfunction is a key contributor to the progression of AKI to CKD, also known as the “AKI-to-CKD” transition. The long-term goal of this application is to define the molecular mechanisms of proximal tubular mitochondrial metabolic dysfunction, leading to dysregulated fatty acid oxidation and CKD. We have identified mitochondrial Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), the rate limiting enzyme for ketogenesis, to be expressed in the kidney in an inducible fashion. Using liver- and kidney-specific Hmgcs2 deletion mouse models, we found that renal HMGCS2 likely acts locally, without contributing to circulating ketones. After LPS challenge, renal HMGCS2 is induced after the initial kidney injury has resolved, suggesting a potential role in late recovery after septic AKI. Kidney-specific Hmgcs2 knockout mice do not exhibit any difference in the early kidney injury response to LPS. However, two months after recovering from acute septic AKI, mice lacking renal Hmgcs2 show increased levels of kidney injury and fibrosis markers compared to wild-type animals. In ischemic kidney injury, kidney HMGCS2 is suppressed both during the early AKI period and in the late fibrotic phase. Mice lacking renal Hmgcs2 develop more acute tubular injury and late fibrosis after ischemic kidney injury. Twenty-four hours after ischemic injury, kidneys lacking Hmgcs2 exhibit decreased expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (Ppargc1a) which encodes PGC1a, a master regulator of mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation. Using a novel mouse model capable of isolating proximal tubule-specific mitochondria, we found that proximal tubular mitochondria lacking HMGCS2 have depressed mitochondrial respiration. Transcriptomic data from kidney biopsies show that HMGCS2 is suppressed across multiple CKD patient cohorts. Thus, renal mitochondrial HMGCS2 deficiency may not only be a marker of kidney disease but could also be pathogenic. Together these data led to the hypothesis that activation of renal ketogenesis is a protective metabolic pathway limiting the development of CKD by promoting mitochondrial homeostasis and maintaining mitochondrial function and fatty acid oxidation. In Aim 1, we examine the mechanism by which renal HMGCS2 deficiency promotes the AKI-to-CKD transition in ischemic and septic AKI. We will explore the extent to which PGC1a suppression promotes CKD progression in the context of HMGCS2 deficiency. In Aim 2, we dissect the role of renal HMGCS2 in maintaining mitochondrial function by analyzing proximal tubular-specific mitochondria. In Aim 3, we differentiate the effect of endogenous liver-derived or exogenous circulating ketones compared to intra-renal ketone production in AKI and CKD.