Document text
Principal Investigator: Alexander Staruschenko
Organization: JAMES A. HALEY VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
The kidneys are highly sensitive to metabolic changes. Metabolic phenotyping uncovered a number
of pathways associated with high blood pressure and kidney diseases, which sheds light on the
complex pathophysiology of hypertension and associated kidney injury. However, the mechanisms
underlying the effects of dietary interventions on kidney function and associated changes in cellular
metabolic intermediates remain incompletely understood. L-lysine is one of the essential amino
acids, which is necessary for many physiological functions. Our recent metabolomics study revealed
that intrarenal levels of L-Lysine are reduced in Dahl salt-sensitive (SS) rats when animals are fed
an HS diet. This provided further evidence that L-Lysine is critical for metabolic states in the kidney.
The main hypothesis of this project is that dietary L-Lysine supplementation significantly enhances
cardiorenal protection via acute inhibition of metabolic load and oxidative stress triggered by
hypertension and renal damage-induced uptake of albumin in proximal tubule (PT) cells and on a
longer scale – via chemically modified entities that provide a sink for essential mitochondrial
metabolism and fatty acid biosynthesis. Specifically, we propose that L-Lysine accumulates in the
kidneys, inhibits PT reabsorption, and promotes excretion of excessively accumulated intrarenal
albumin. These effects of L-Lysine, in conjunction with strong diuretic and natriuretic properties,
leads to the protection of PT from metabolic stress. Furthermore, our evidence supports that lysine
malonylation (recently described post-translational modification) plays an important role in salt-
induced hypertension and kidney injury. Proposed here research strategy represents a pioneering
effort to understand the mechanisms regulating metabolic states in the kidney and further
pathological changes associated with altered PT function during the development of salt-induced
hypertension and chronic kidney disease. Mechanistic insight into the protective effects of L-Lysine
and the contribution of Lysine malonylation in these mechanisms will be uncovered. Several
innovative approaches and unique rat models will be used to test the following Specific Aims:
Aim 1 will define the protective effects of L-Lysine dietary management on PT reabsorption, renal
oxidative stress, and the development of renal damage in salt-sensitive hypertension. The
hypothesis that Slc7a9 is a key transporter of L-Lysine in PT will also be tested in this aim.
Aim 2 will establish the contribution of the Lysine malonylation metabolic pathway in the control of
free fatty acid metabolism and mitochondria function. A combination of pharmacological (by using
potent MCD inhibitor CBM 301940) and genetic (novel SSMlycd-/- rat model) approaches will be further
utilized to understand the role of Malonyl-Lysine in mitochondrial fatty acid oxidation and the
regulation of malonyl-CoA in kidney function.
Terms: <ATP Synthesis><ATP Synthesis Pathway><Active Biologic Transport><Active Biological Transport><Active Transport><Acute><Albumins><Animal Feed><Blood Plasma><Caring><Cell Body><Cells><Chemicals><Chronic><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Common Rat Strains><Complex><Dahl Hypertensive Rats><Dahl Salt-Sensitive Rats><Development><Dietary Intervention><Dietary Supplementation><Diuretics><Dysfunction><Enzyme Gene><Enzymes><Essential Amino Acids><Excretory function><Fatty Acid Metabolism Pathway><Filtration><Filtration Fractionation><Free Fatty Acids><Functional disorder><Generalized Growth><Genetic><Growth><Hypertension><Immune system><Injury to Kidney><Intermediary Metabolism><Kidney><Kidney Diseases><Kidney Urinary System><L-Lysine><Long-Term Effects><Longterm Effects><Lysine><Malonyl CoA><Malonyl Coenzyme A><Mediating><Medical><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolic stress><Metabolic syndrome><Metabolism><Mitochondria><Modeling><Nephropathy><Nonesterified Fatty Acids><Nutrition Interventions><Nutritional Interventions><Oxidative Stress><Pathogenicity><Pathologic><Pathway interactions><Physiologic><Physiological><Physiopathology><Plasma><Plasma Serum><Play><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Prevention><Production><Property><Protein Modification><Rat><Rats Mammals><Rattus><Regulation><Renal Disease><Renal function><Reporting><Research><Reticuloendothelial System, Serum, Plasma><Risk><Role><Social Support System><Supplementation><Support System><Testing><Therapeutic><Tissue Growth><Uphill Transport><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Veterans><absorption><animal food><chronic kidney disease><damage to kidney><developmental><diet intervention><diet supplementation><dietary><excretion><experiment><experimental research><experimental study><experiments><fatty acid biosynthesis><fatty acid metabolism><fatty acid oxidation><glomerular filtration><high blood pressure><high salt diet><high sodium diet><hyperpiesia><hyperpiesis><hypertensive><hypertensive disease><hypertensive disorder><improved><inhibitor><innovate><innovation><innovative><insight><kidney damage><kidney disorder><kidney function><kidney injury><men><metabolic phenotype><metabolism measurement><metabolomics><metabonomics><metabotype><mitochondrial><mitochondrial metabolism><natriuretic><novel><ontogeny><pathophysiology><pathway><pharmacologic><protective effect><renal><renal damage><renal disorder><renal injury><salt hypertension><salt induced hypertension><salt sensitive hypertension><saluretic><social role><uptake>