Renal metabolism and hypertension

Abstract

Hypertension is a leading risk factor for disease burden worldwide. The kidneys, which have a high specific metabolic rate, play an essential role in the long-term regulation of arterial blood pressure. In this review, we discuss the emerging role of renal metabolism in the development of hypertension. Renal energy and substrate metabolism is characterized by several important and, in some cases, unique features. Recent advances suggest that alterations of renal metabolism may result from genetic abnormalities or serve initially as a physiological response to environmental stressors to support tubular transport, which may ultimately affect regulatory pathways and lead to unfavorable cellular and pathophysiological consequences that contribute to the development of hypertension.

Fig. 1. Renal metabolism and nephron segments.

A Major metabolic pathways in the kidney. To make the figure comprehensible, only rate-limiting or key enzymes are shown, and arrows that contain multiple enzymatic steps are shown as dashed arrows. The box surrounded by the dashed line indicates mitochondria. FBP fructose 1,6-bisphosphatase, PEPCK-C cytosolic phosphoenolpyruvate carboxykinase, HK hexokinase, PFK-1 phosphofructokinase-1, PK pyruvate kinase, CPT1 carnitine palmitoyltransferase I, HMGCS2 mitochondrial HMG-CoA synthetase, SCOT succinyl-CoA:3-ketoacid-CoA transferase, GLS glutaminase, CS citrate synthase, IDH isocitrate dehydrogenase, α-KGDH α-Ketoglutarate dehydrogenase. B Examples of approved or investigational drugs targeting the metabolic pathways. C Major metabolic pathways in nephron segments. Colors of bars correspond to the colors of pathway names in panel A. The percentages indicate the percent of the filtered sodium reabsorbed or excreted.

Fig. 2. Renal metabolic mechanisms of hypertension in Dahl salt-sensitive (SS) rats.

A Renal metabolic mechanisms of hypertension. This figure is primarily based on data obtained from analyses of the renal medulla or the medullary thick ascending limb of the loop of Henle in SS rats. Some of the indicated changes also occur in the renal cortex. The blue arrows represent increased or decreased content (or activity) in SS rats relative to salt-insensitive rats, including SS-13^BN rats. The red arrows represent increased or decreased content (or activity) in SS rats fed a high-salt diet. Blue pentagons represent sites of reactive oxygen species generation. Black arrow and inverted T mark (⊥) represent positive and negative influence, respectively. Some of these regulatory relations and their causal role in the development of hypertension remain to be tested in the specific context of SS kidneys. TCA tricarboxylic acid cycle, OGDH α-ketoglutarate dehydrogenase, FH, fumarase; MDH, malic dehydrogenase; ASS, argininosuccinate synthetase; ASL, argininosuccinate lyase; AST, aspartate aminotransferase, NOS nitric oxide synthase, HK hexokinase, PFK phosphofructokinase, G6PD glucose-6-phosphate dehydrogenase, 6GPD 6-phosphogluconate dehydrogenase, GSH glutathione, GSSG glutathione disulfide, GR glutathione reductase, GPx glutathione peroxidase, NKCC2 Na–K-2Cl cotransporter, SOD superoxide dismutase, CAT catalase, MBF medullary blood flow. B Examples of chemical inhibitors of components of the metabolic mechanisms shown in panel (A). Other inhibitors may be available, and the inhibitors listed may have additional targets. ETC electron transport chain, L-NAME L-N^G-nitro arginine methyl ester.

Fig. 3. The proposed overall mechanism by which renal energy and substrate metabolism contribute to the development of hypertension.

It is well-established that genetic and environmental factors influence renal tubular transport and hemodynamics, which, in turn, contribute to the development of hypertension and cause changes in renal energy and substrate metabolism. Recent advances in human and animal model research indicate that renal energy and substrate metabolism may also influence the development of hypertension, which may be mediated by novel effects of renal energy and substrate metabolism on regulatory substances including NO and ROS and subsequent effects on renal tubular transport and hemodynamics. Mito mitochondria, GWAS SNPs blood pressure-associated single-nucleotide polymorphisms identified by genome-wide association studies, TCA tricarboxylic acid, NO nitric oxide, ROS reactive oxygen species.