Effects of melatonin on suppression of renal scarring in experimental model of pyelonephritis

doi:10.1016/j.urology.2005.12.013

Urology

Volume 67, Issue 6, June 2006, Pages 1315-1319

https://doi.org/10.1016/j.urology.2005.12.013 Get rights and content

Abstract

Objectives

To determine the effects of melatonin combined with antibiotic administration on the suppression of renal scarring in an experimental pyelonephritis model.

Methods

The control group underwent a sham operation without infection. In the other groups, treatment began 72 hours after direct bacterial inoculation. In the no-treatment group, rats received daily intraperitoneal injections of saline. In the antibiotic-only group, the rats were treated only with ceftriaxone intramuscularly at a dose of 50 mg/kg once daily for 5 days. In the melatonin-only group, only 20 mg/kg of melatonin once daily was given by intraperitoneal injection for 5 days. In the antibiotic plus melatonin group, melatonin and ceftriaxone were administered at the same dosages and duration as for the single-modality treatment groups. After 6 weeks, the kidneys were removed for malondialdehyde measurements and histopathologic examination (inflammatory response and cicatrization).

Results

Melatonin only (134.25 ± 13.42) and antibiotic plus melatonin treatment (122.62 ± 8.91) caused a marked reduction in the mean malondialdehyde values compared with no treatment (214.12 ± 17.77) and antibiotic-only treatment (161.37 ± 16.03), with no significant difference compared with that of the control group (120.75 ± 9.83). Histopathologically, in the no-treatment group, the severity of scarring correlated directly with the severity of inflammation (r = 0.93). No significant differences were found in the renal scarring scores in rats receiving no treatment and those treated only with antibiotic or melatonin. In the antibiotic plus melatonin treatment group, the cicatrization score was not statistically different from that of the control group.

Conclusions

When combined with antibiotics, melatonin causes a significant inhibition of malondialdehyde production and neutrophil infiltration caused by acute pyelonephritis in an experimental rat model, and these are responsible for the protective effect of melatonin against renal damage, preventing renal scarring formation.

Section snippets

Animals

A total of 40 male Sprague-Dawley rats weighing between 250 and 300 g were kept in specific pathogen-free conditions at room temperature (22° ± 2°C) using a 12/12-hour light/dark cycle and provided with commercially available rat chow and tap water ad libitum. The Karadeniz Technical University School of Medicine Animal Care and Ethics Committee approved the study.

Bacteria

The Escherichia coli strain UTI 36, isolated from a previous patient with confirmed acute pyelonephritis and phenotyped for the

Histopathologic Examination

Figure 1 shows the mean scores of the two histopathologic parameters for each group. Analysis of the no-treatment group demonstrated that the severity of scarring correlated directly with the severity of inflammation (r = 0.93, P = 0.001). A statistically significant difference was found among the groups for each parameter (P <0.0005).

Comment

Sufficient evidence exists that antioxidants, by inhibition or reduction of free oxygen radicals, offer protection against pyelonephritis-induced renal damage.1, 5 The most commonly used and most thoroughly experimentally studied antioxidants are vitamins (ie, ascorbic acid, tocopherol, and beta-carotene).1, 5 However, in addition to serving in the direct detoxification of free radicals, they also interact in recycling processes to generate reduced forms of the vitamins. The vitamins also

Conclusions

We have shown that, when combined with antibiotics, melatonin therapy in an experimental model of pyelonephritis provides protection against renal scarring through its broad spectrum of antioxidative and important anti-inflammatory properties, even if treatment is delayed. This observation is potentially clinically useful when the low toxicity in children is considered. However, additional studies are needed to determine the optimal dose and duration, as well as the long-term results.

References (28)

R.T. Bennett et al.
Suppression of renal inflammation with vitamins A and E in ascending pyelonephritis in rats
J Urol
(1999)
M. Haraoka et al.
Suppression of renal scarring by prednisolone combined with ciprofloxacin in ascending pyelonephritis in rats
J Urol
(1994)
H.G. Pohl et al.
Adjunctive oral corticosteroids reduce renal scarringthe piglet model of reflux and acute experimental pyelonephritis
J Urol
(1999)
A. Huang et al.
Ibuprofen combined with antibiotics suppresses renal scarring due to ascending pyelonephritis in rats
J Urol
(1999)
A. Yağmurlu et al.
Preventive effect of pentoxifylline on renal scarring in rat model of pyelonephritis
Urology
(2003)
M.J. Drake et al.
Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement
J Urol
(2004)
H. Okur et al.
The role of infection and free oxygen radical damage in reflux nephropathyan experimental study
J Urol
(2003)
J. Roberts
Vesicoureteral reflux and pyelonephritis in the monkeya review
J Urol
(1992)
M.R. McCall et al.
Can antioxidant vitamins materially reduce oxidative damage in humans?
Free Rad Biol Med
(1999)
J.A. Roberts et al.
Immunology of pyelonephritis in the primate model. V. Effect of superoxide dismutase
J Urol
(1982)

B. Jakobsson et al.

Renal scarring after acute pyelonephritis

Arch Dis Child

(1994)

S. Kavukçu et al.

The role of vitamin A in preventing renal scarring secondary to pyelonephritis

BJU Int

(1999)

E. Gitto et al.

Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin

J Pineal Res

(2004)

F. Fulia et al.

Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newbornsreduction by melatonin

J Pineal Res

(2001)

Cited by (22)

Effect of melatonin on oxidative stress indicators in animal models of fibrosis: A systematic review and meta-analysis
2023, Free Radical Biology and Medicine
Imbalance of oxidative stress has been detected in a range of fibrotic diseases. Melatonin as an indoleamine hormone plays an important role in regulating the circadian rhythm of human, while in recent years, its antioxidant effect has also attracted increasing attention. This study aimed to perform a systematic review and meta-analysis to comprehensively evaluate the antioxidant effect of melatonin in animal models of fibrosis.
The PubMed, Cochrane Library, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang database, China Science and Technology Journal Database (VIP), and SinoMed databases were searched from inception to March 1st, 2022 to retrieve eligible studies that evaluated the effect of melatonin supplementation on the levels of malondialdehyde (MDA), lipid peroxidation (LPO), nitric oxide (NO), superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), and catalase (CAT) in animal models of fibrosis.
A total of 64 studies were included in this meta-analysis. The results showed that melatonin supplementation significantly reduced the levels of oxidative indicators including MDA (P < 0.00001), LPO (P < 0.00001) and NO (P < 0.0001), and elevated the levels of antioxidant indicators including GSH (P < 0.00001), GPx (P < 0.00001) and SOD (P < 0.00001) in fibrotic diseases.
Our research findings showed that melatonin supplementation could significantly reduce the levels of oxidative indicators including MDA, LPO and NO and elevate the levels of antioxidant indicators including GSH, GPx and SOD so as to correct oxidative stress in animal models of fibrosis. However, no significant changes were observed in CAT level. More clinical studies are needed to further confirm the beneficial role of melatonin in fibrotic diseases.
Preventive effect of phosphodiesterase 5 inhibitor Tadalafil on experimental post-pyelonephritic renal injury in rats
2014, Journal of Surgical Research
Citation Excerpt :
It may take at least 48 more hours for the specific diagnostic signs of the acute PN to appear [22]. On the other hand, animal studies have revealed that antibiotics and antioxidants would fail to reduce renal scarring if the treatment was started 72 h after bacterial inoculation [23]. In this situation, a golden period of time is lost that could be saved by the immediate administration of anti-oxidant agents [24].
To evaluate the effects of Tadalafil, a phosphodiesterase 5 enzyme inhibitor, on Escherichia coli–induced renal damage in an acute pyelonephritis (PN) rat model.
Experimental PN was induced in 32 Wistar rats, and four groups were formed: group 1 (no treatment), group 2 (antibiotic), group 3 (Tadalafil), and group 4 (antibiotic + Tadalafil). Antibiotic was given on days 3 to 8, and Tadalafil was administered between days 0 and 28 of bacterial inoculation. Half of the rats were killed on the ninth day (early period) and histopathological parameters, immunohistochemical renal fibrosis markers, and oxidant/antioxidant system activities were evaluated. The rest of the rats were killed at the sixth week of the study and evaluated for histopathological parameters and renal fibrosis markers.
Inflammatory activity was significantly milder in rats treated with antibiotic + Tadalafil versus no treatment group both in the early and late periods. In the late period, interstitial fibrosis or tubular atrophy was lower in the antibiotic + Tadalafil group versus the no treatment and antibiotic groups, and in Tadalafil versus antibiotic group. Tadalafil administration significantly reduced renal malondialdehyde and nitric oxide levels and enhanced superoxide dismutase and catalase activities. In addition, circulating tumor necrosis factor α, interleukin 1β was greatly reduced in Tadalafil group versus the no treatment group.
We have provided the first evidence that phosphodiesterase 5 enzyme inhibitor Tadalafil ameliorates circulating inflammatory cytokines, reverses oxidant/antioxidant dysfunction and eventually possesses an overall protective effect on renal tissue from Escherichia coli–induced PN-related kidney injury. Phophodieterase 5 inhibitor might be a novel therapeutic target for PN.
Inflammatory pre-conditioning of mesenchymal multipotent stromal cells improves their immunomodulatory potency in acute pyelonephritis in rats
2013, Cytotherapy
Citation Excerpt :
MMSCs might be an appropriate treatment of pyelonephritis as an inflammatory disease. It is now generally believed that the renal damage caused by pyelonephritis is mainly proportional to the extent of the inflammation associated with the infection, rather than of actual bacterial growth in the kidney (35–37). The increase in the expression of TNF-α and interleukin-1β after renal inflammation may be responsible for recruitment from the local vasculature of neutrophils that are potent generators of ROS.
Acute pyelonephritis is one of the most frequent infectious diseases of the urinary tract and a leading cause of kidney failure worldwide. One strategy for modulating excessive inflammatory responses in pyelonephritis is administration of mesenchymal multipotent stromal cells (MMSCs).
The putative protective effect of injection of MMSCs against experimental acute pyelonephritis was examined. We used in vivo experimental model of APN where bacteria are introduced in the bladder of rat. Three days after, intravenous injection of MMSCs was done. On the 7th day blood samples and kidneys were taken for further analysis.
We found obvious signs of oxidative stress and inflammation in the kidney in acute pyelonephritis in rats. Particularly, pro-inflammatory cytokine tumor necrosis factor-α levels, malondialdehyde, nitrite and myeloperoxidase activity were significantly increased. Histologic evaluation revealed numerous attributes of inflammation and tissue damage in the kidney. Treatment with MMSCs caused a remarkable decrease of all of these pathologic signs in renal tissue. Also, activated leukocytes induced pre-conditioning-like signaling in MMSCs. We showed alterations of expression or activity of inducible nitric oxide synthase, transforming growth factor-β, matrix metalloproteinase-2 and glycogen synthase kinase-3β, which could mediate immunomodulation and protective effects of MMSCs. This signaling could be characterized as inflammatory pre-conditioning.
The beneficial capacity of MMSCs to alleviate renal inflammation was more pronounced when pre-conditioned MMSCs were used. This approach could be used to prime MMSCs with different inflammatory modulators to enhance their engraftment and function in an immunoprotected fashion.
Potential for the sanatorium-resort rehabilitation for children with chronic pyelonephritis, associated with the background of melatonin secretion rhythm inversion
2020, Pediatriya - Zhurnal im G.N. Speranskogo
Investigation of the Optimum Preparation of Peach Gum Polysaccharides and the in Vivo and in Vitro Therapeutic Effects on Acute Pyelonephritis
2019, Evidence-based Complementary and Alternative Medicine
Corticosteroids for renal scar prevention in children with acute pyelonephritis
2017, Canadian Family Physician

View all citing articles on Scopus

View full text

Basic scienceEffects of melatonin on suppression of renal scarring in experimental model of pyelonephritis

Abstract

Objectives

Methods

Results

Conclusions

Section snippets

Animals

Bacteria

Histopathologic Examination

Comment

Conclusions

J Urol

J Urol

J Urol

J Urol

Urology

J Urol

J Urol

J Urol

Free Rad Biol Med

J Urol

Renal scarring after acute pyelonephritis

Arch Dis Child

The role of vitamin A in preventing renal scarring secondary to pyelonephritis

BJU Int

Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin

J Pineal Res

Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newbornsreduction by melatonin

J Pineal Res

Basic science
Effects of melatonin on suppression of renal scarring in experimental model of pyelonephritis