Mitochondrial Dysfunction and Altered Renal Metabolism in Dahl Salt-Sensitive Rats

Abstract

Background/Aims: The kidney plays a critical role in the control of blood pressure and its elevation in salt-induced hypertension. Mitochondrial dysfunction, especially in energy metabolism, has been associated with hypertension. Here, we aimed to investigate mitochondrial function and metabolic features in renal mitochondria of Dahl salt-sensitive (SS) rats to gain further insight into the relationship between mitochondrial metabolism and predisposition to hypertension. Methods: In this study, SS rats fed low-salt (LS) or high-salt (HS) diets were used to investigate mitochondrial function and metabolism including mitochondrial enzyme activities, pyridine nucleotides, metabolites, and oxidative stress by biochemical analysis and gas chromatography-mass spectrometer (GC-MS). Results: Significantly lower activity levels of fumarase, isocitrate dehydrogenase and succinyl-CoA synthetase were observed in renal mitochondria of SS rats compared with SS.13^BN control rats fed LS diets. Intra-mitochondrial pyridine nucleotide content and mitochondrial metabolism were adversely affected in SS rats. In accordance with this, reduced ATP production, Δψm, and superoxide dismutase (SOD) activity were also observed in mitochondria of the renal medulla and cortex of SS rats. Moreover, ATP production was further impaired and oxidative stress was increased, confirming that the mitochondria of SS rats fed HS diets were dysfunctional compared to those of rats fed LS diets. Conclusions: Our data demonstrated that the renal mitochondria of SS rats exhibited complicated metabolic alteration and dysfunction in low-salt diets, and high-salt diets aggravated these dysfunctions. Thus, these results may be associated with renal dysfunction, which, in turn, would help in understanding the development of salt-sensitive hypertension.

High-Salt Attenuates the Efficacy of Dapagliflozin in Tubular Protection by Impairing Fatty Acid Metabolism in Diabetic Kidney Disease

“…Besides, high intake of salt further exacerbates the imbalance between these factors in diabetic mice, leading to aggravation of kidney damage. Previous studies also suggested that high-salt aggravated renal mitochondrial dysfunctions (Wang et al, 2017). These data highlight that we may prevent mitochondrial dysfunction by reducing dietary salt intake, thereby restoring the balance of renal tubular fatty acid metabolism and improving renal function.…”

Renal metabolism and hypertension

“…similar between SS and SS.13 BN rats on a 0.4% salt diet, while mitochondrial membrane potential and ATP production rate are lower in SS rats 63 . Treatment with a 4% NaCl diet for 7 or 21 days resulted in lower ratios of ATP/ADP, GTP/GDP, and NADH/ NAD + in the glomeruli, but not the cortical tissue, of SS rats 64 .…”

Renal Glomerular Mitochondria Function in Salt-Sensitive Hypertension

“…We believe that these discrepancies may be attributed to mechanistic dissimilarities in the origin and progression of hypertension in SHR and Dahl SS rats. A recent manuscript by Wang et al (2017) established that renal mitochondria from Dahl SS rats fed HS diet (8%, 2 weeks) exhibit a lower activity of fumarase, isocitrate dehydrogenase, and succinyl-CoA synthase compared with SS.13BN salt-resistant control rats, as well as reduced ATP production, membrane potential, and SOD activity. Our data indicated that similar mitochondrial impairment manifested in Dahl SS rats when a lesser salt challenge was introduced (4%, 3 weeks).…”

“…In 2014, He et al (2014) demonstrated that mitochondrial abnormalities can be observed in the mTAL of SS rats before the development of histologically detectable injury. Later, Wang et al (2017) provided evidence that renal mitochondria of Dahl SS rats displayed metabolic alterations and dysfunctions, aggravated by an increase in salt intake. Through transcriptomic analyses of renal medullary biological pathways, they established that mitochondrial TCA cycle and cell energetics are crucial for the molecular networks relevant to salt-sensitivity Evans et al, 2018).…”