Effect of endogenous hydrogen sulfide inhibition on structural and functional renal disturbances induced by gentamicin

Abstract

Animal models of gentamicin nephrotoxicity present acute tubular necrosis associated with inflammation, which can contribute to intensify the renal damage. Hydrogen sulfide (H2S) is a signaling molecule involved in inflammation. We evaluated the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H2S formation, on the renal damage induced by gentamicin. Male Wistar rats (N = 8) were injected with 40 mg/kg gentamicin (im) twice a day for 9 days, some of them also received PAG (N = 8, 10 mg·kg−1·day−1, ip). Control rats (N = 6) were treated with saline or PAG only (N = 4). Twenty-four-hour urine samples were collected one day after the end of these treatments, blood samples were collected, the animals were sacrificed, and the kidneys were removed for quantification of H2S formation and histological and immunohistochemical studies. Gentamicin-treated rats presented higher sodium and potassium fractional excretion, increased plasma creatinine [4.06 (3.00; 5.87) mg%] and urea levels, a greater number of macrophages/monocytes, and a higher score for tubular interstitial lesions [3.50 (3.00; 4.00)] in the renal cortex. These changes were associated with increased H2S formation in the kidneys from gentamicin-treated rats (230.60 ± 38.62 µg·mg protein−1·h−1) compared to control (21.12 ± 1.63) and PAG (11.44 ± 3.08). Treatment with PAG reduced this increase (171.60 ± 18.34), the disturbances in plasma creatinine levels [2.20 (1.92; 4.60) mg%], macrophage infiltration, and score for tubular interstitial lesions [2.00 (2.00; 3.00)]. However, PAG did not interfere with the increase in fractional sodium excretion provoked by gentamicin. The protective effect of PAG on gentamicin nephrotoxicity was related, at least in part, to decreased H2S formation.

Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway

“…Although most of the literature supports the notion that hydrogen sulfide protects against oxidative stress and thus generally also against renal disease (Koning et al , ; Lobb et al , ), some recent studies suggest that treatment with the CSE inhibitor propargylglycine (PAG) inhibits endogenous H 2 S production and increases antioxidant enzyme expression while significantly improving renal function reducing renal damage, fibrosis, and inflammation. Another study demonstrated that PAG‐treated animals exhibited significantly improved renal function and decreased renal necrosis as well as decreased ROS production, oxidative stress, and caspase activation following gentamicin treatment (Francescato et al , ).…”

Correlation of Lower Concentrations of Hydrogen Sulfide with Atherosclerosis in Chronic Hemodialysis Patients with Diabetic Nephropathy

“…Numerous present studies in animals and humans have shown H 2 S possess important physiological and pathophysiologic functions, such as the regulation of blood pressure [25], inflammation [26], renal damage [27], neurodegenerative diseases [28,29,] and metabolic disorders, including obesity and diabetes [30]. Liu et al found that H 2 S can improve wound healing by restoring endothelial progenitor cell functions and activation of Ang-1 in type 2 diabetic mice [31].…”

Hydrogen sulfide in renal physiology, disease and transplantation – The smell of renal protection

“…In contrast to the adverse impact of relative H2S deficiency in models of renal disease described so far, in rat models of cisplatin, adriamycin and gentamicin-induced nephrotoxicity endogenous H2S has been reported to aggravate renal damage [93][94][95][96]. However, this assumption was based on the finding that PAG reduced renal damage caused by injection of these nephrotoxic substances.…”