Delayed exercise training improves obesity-induced chronic kidney disease by activating ampk pathway in high-fat diet-fed mice

Exercise training is now recognized as an interesting therapeutic strategy in managing obesity and its related disorders. However, there is still a lack of knowledge about its impact on obesity-induced chronic kidney disease (CKD). Here, we investigated the effects of a delayed protocol of endurance exercise training (EET) as well as the underlying mechanism in obese mice presenting CKD. Mice fed a high-fat diet (HFD) or a low-fat diet (LFD) for 12 weeks were subsequently submitted to an 8-weeks EET protocol. Delayed treatment with EET in obese mice prevented body weight gain associated with a reduced calorie intake. EET intervention counteracted obesity-related disorders including glucose intolerance, insulin resistance, dyslipidaemia and hepatic steatosis. Moreover, our data demonstrated for the first time the beneficial effects of EET on obesity-induced CKD as evidenced by an improvement of obesity-related glomerulopathy, tubulo-interstitial fibrosis, inflammation and oxidative stress. EET also prevented renal lipid depositions in the proximal tubule. These results were associated with an improvement of the AMPK pathway by EET in renal tissue. AMPK-mediated phosphorylation of ACC and ULK-1 were particularly enhanced leading to increased fatty acid oxidation and autophagy improvement with EET in obese mice

Restored nitric oxide bioavailability reduces the severity of acute-to-chronic transition in a mouse model of aristolochic acid nephropathy

Aristolochic Acid (AA) nephropathy (AAN) is a progressive tubulointerstitial nephritis characterized by an early phase of acute kidney injury (AKI) leading to chronic kidney disease (CKD). The reduced nitric oxide (NO) bioavailability reported in AAN might contribute to renal function impairment and progression of the disease. We previously demonstrated that L-arginine (L-Arg) supplementation is protective in AA-induced AKI. Since the severity of AKI may be considered a strong predictor of progression to CKD, the present study aims to assess the potential benefit of L-Arg supplementation during the transition from the acute phase to the chronic phase of AAN. C57BL/6J male mice were randomly subjected to daily i.p. injections of vehicle or AA for 4 days. To determine whether renal AA-induced injuries were linked to reduced NO production, L-Arg was added to drinking water from 7 days before starting i.p. injections, until the end of the protocol. Mice were euthanized 5, 10 and 20 days after vehicle or AA administration. AA-treated mice displayed marked renal injury and reduced NO bioavailability, while histopathological features of AAN were reproduced, including interstitial cell infiltration and tubulointerstitial fibrosis. L-Arg treatment restored renal NO bioavailability and reduced the severity of AA-induced injury, inflammation and fibrosis. We concluded that reduced renal NO bioavailability contributes to the processes underlying AAN. Furthermore, L-Arg shows nephroprotective effects by decreasing the severity of acute-to-chronic transition in experimental AAN and might represent a potential therapeutic tool in the future.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Sex differences in obesity-induced renal lipid accumulation revealed by lipidomics: a role of adiponectin/AMPK axis

Abstract Background Sex differences have been observed in the development of obesity-related complications in patients, as well as in animal models. Accumulating evidence suggests that sex-dependent regulation of lipid metabolism contributes to sex-specific physiopathology. Lipid accumulation in the renal tissue has been shown to play a major role in the pathogenesis of obesity-induced kidney injury. Unlike in males, the physiopathology of the disease has been poorly described in females, particularly regarding the lipid metabolism adaptation. Methods Here, we compared the lipid profile changes in the kidneys of female and male mice fed a high-fat diet (HFD) or low-fat diet (LFD) by lipidomics and correlated them with pathophysiological changes. Results We showed that HFD-fed female mice were protected from insulin resistance and hepatic steatosis compared to males, despite similar body weight gains. Females were particularly protected from renal dysfunction, oxidative stress, and tubular lipid accumulation. Both HFD-fed male and female mice presented dyslipidemia, but lipidomic analysis highlighted differential renal lipid profiles. While both sexes presented similar neutral lipid accumulation with obesity, only males showed increased levels of ceramides and phospholipids. Remarkably, protection against renal lipotoxicity in females was associated with enhanced renal adiponectin and AMP-activated protein kinase (AMPK) signaling. Circulating adiponectin and its renal receptor levels were significantly lower in obese males, but were maintained in females. This observation correlated with the maintained basal AMPK activity in obese female mice compared to males. Conclusions Collectively, our findings suggest that female mice are protected from obesity-induced renal dysfunction and lipotoxicity associated with enhanced adiponectin and AMPK signaling compared to males

Experimental Aristolochic Acid Nephropathy: A Relevant Model to Study AKI-to-CKD Transition

Aristolochic acid nephropathy (AAN) is a progressive tubulointerstitial nephritis caused by the intake of aristolochic acids (AA) contained in Chinese herbal remedies or contaminated food. AAN is characterized by tubular atrophy and interstitial fibrosis, characterizing advanced kidney disease. It is established that sustained or recurrent acute kidney injury (AKI) episodes contribute to the progression of CKD. Therefore, the study of underlying mechanisms of AA-induced nephrotoxicity could be useful in understanding the complex AKI-to-CKD transition. We developed a translational approach of AKI-to-CKD transition by reproducing human AAN in rodent models. Indeed, in such models, an early phase of acute tubular necrosis was rapidly followed by a massive interstitial recruitment of activated monocytes/macrophages followed by cytotoxic T lymphocytes, resulting in a transient AKI episode. A later chronic phase was then observed with progressive tubular atrophy related to dedifferentiation and necrosis of tubular epithelial cells. The accumulation of vimentin and αSMA-positive cells expressing TGFβ in interstitial areas suggested an increase in resident fibroblasts and their activation into myofibroblasts resulting in collagen deposition and CKD. In addition, we identified 4 major actors in the AKI-to-CKD transition: (1) the tubular epithelial cells, (2) the endothelial cells of the interstitial capillary network, (3) the inflammatory infiltrate, and (4) the myofibroblasts. This review provides the most comprehensive and informative data we were able to collect and examines the pending questions.info:eu-repo/semantics/publishe

Effect of L-arginine supplementation on renal function at days 5, 10 and 20 in CTL, AA and AA+L-Arg mice.

<p>Effect of L-arginine supplementation on renal function at days 5, 10 and 20 in CTL, AA and AA+L-Arg mice.</p

Effect of L-arginine supplementation on Sirius Red staining at days 5, 10 and 20 in CTL, AA and AA+L-Arg mice.

<p>Representative photographs of picrosirius red stained kidney sections (x400) from CTL (<b>A,D,G</b>), AA (<b>B,E,H</b>) and AA+L-Arg (<b>C,F,I</b>) mice at days 5, 10 and 20. Scale bar = 50 μm. Real-time quantitative PCR for <i>ColI</i> (<b>J</b>) and <i>ColIII</i> (<b>K</b>) mRNA expression was performed with kidney tissue from CTL, AA and AA+L-Arg mice normalized against <i>18S</i> Quantitative analysis of picrosirius red expression in CTL, AA and AA+L-Arg mice at days 5, 10 and 20 (<b>L</b>). Statistical analysis was performed using two-way ANOVA followed by Holm-Sidak test. Data are presented as means ± SEM; <i>n</i> = 8 in each group. **<i>P</i> ≤ 0,01 <i>vs</i> CTL mice, ***<i>P</i> ≤ 0,001 <i>vs</i> CTL mice, ^#<i>P</i> ≤ 0,05 <i>vs</i> AA mice, ^##<i>P</i> ≤ 0,01 <i>vs</i> AA mice and ^###<i>P</i> ≤ 0,001 <i>vs</i> AA mice.</p

Urinary NOx and cGMP excretions at days 5, 10 and 20 in CTL, AA and AA+L-Arg mice and relative kidney expression of nitric oxide synthases mRNA (2^{-Δ ΔCT}) at days 5, 10 and 20 in CTL, AA and AA+L-Arg mice.

<p>(<b>A</b>) Urinary nitrite/nitrate (NOx) concentrations in CTL, AA and AA+L-Arg mice. (<b>B</b>) Urinary cGMP concentrations in CTL, AA and AA+L-Arg mice. Real-time quantitative PCR for <i>endothelial nitric oxide synthase</i> (<i>eNOS</i>) (<b>C</b>), <i>inducible nitric oxide synthase</i> (<i>iNOS</i>) (<b>D</b>) and <i>neuronal nitric oxide synthase</i> (<i>nNOS</i>) (<b>E</b>) mRNA expression was performed on kidney tissue from CTL, AA and AA+L-Arg mice normalized against <i>18S</i>. Data are presented as means ± SEM; <i>n</i> = 8 in each group. Statistical analysis were performed by two-way ANOVA followed by Holm-Sidak test. *<i>P</i> ≤ 0,05 <i>vs</i> CTL mice, **<i>P</i> ≤ 0,01 <i>vs</i> CTL mice, ^## <i>P</i> ≤ 0,01 <i>vs</i> AA mice.</p

Sequences of the primers used for qRT-PCR.

<p>Sequences of the primers used for qRT-PCR.</p

Effect of L-arginine supplementation on tubular injury score and on relative kidney expression of Neutrophil Gelatinase-Associated Lipocalin (<i>NGAL</i>) mRNA at days 5, 10 and 20 in CTL, AA and AA+L-Arg mice.

<p>Tubular injury in CTL, AA and AA+L-Arg mice. Representative photographs of hemalun, Luxol fast blue and Periodic Acid Schiff stained kidney sections (x400) from CTL (<b>A,D,G</b>), AA (<b>B,E,H</b>) and AA+L-Arg (<b>C,F,I</b>) mice at days 5, 10 and 20. Necrotic tubules (red) with cell debris in tubular lumens are visible in AA and AA+L-Arg treated mice at days 5 and 10 and cystic tubules (green) are visible in AA and AA+L-Arg treated mice at days 10 and 20. Scale bar = 50 μm. Real-time quantitative PCR for <i>Neutrophil Gelatinase-Associated Lipocalin</i> (<i>NGAL</i>) mRNA expression was performed with kidney tissue from CTL, AA and AA+L-Arg mice normalized against <i>18S</i> (<b>J</b>). Quantitative analysis of tubular injury in CTL, AA and AA+L-Arg mice at days 5, 10 and 20 (<b>K</b>). Statistical analysis was performed using two-way ANOVA followed by Holm-Sidak test. Data are presented as means ± SEM; <i>n</i> = 8 in each group. ***<i>P</i> ≤ 0,001 <i>vs</i> CTL mice, ^#<i>P</i> ≤ 0,05 <i>vs</i> AA mice, ^##<i>P</i> ≤ 0,05 <i>vs</i> AA mice and ^###<i>P</i> ≤ 0,001 <i>vs</i> AA mice.</p

Effect of L-arginine supplementation on relative kidney expression of inflammatory cytokines; interleukin 6 (<i>IL6</i>), interleukin 1β (<i>IL1β</i>) and tumor necrosis factor α (<i>TNFα</i>) mRNA (2^{-Δ ΔCT}) and on on interstitial infiltration of macrophages and lymphocytes at days 5, 10 and 20 in CTL, AA and AA+L-Arg mice.

<p>Real-time quantitative PCR for <i>interleukin 6</i> (<i>IL6</i>) (<b>A</b>), <i>interleukin 1β</i> (<i>IL1β</i>) (<b>B</b>) and <i>tumor necrosis factor α</i> (<i>TNFα</i>) (<b>C</b>) mRNA expression was performed on kidney tissue from CTL, AA and AA+L-Arg mice normalized against <i>18S</i>. Macrophage (<b>D</b>) and lymphocyte (<b>E</b>) accumulation within the interstitium of kidney from CTL, AA and AA+L-Arg mice at days 5, 10 and 20. Statistical analysis was performed using two-way ANOVA followed by Holm-Sidak test. Data are presented as means ± SEM; <i>n</i> = 8 in each group. *<i>P</i> ≤ 0,05 <i>vs</i> CTL mice, **<i>P</i> ≤ 0,01 <i>vs</i> CTL mice, ***<i>P</i> ≤ 0,001 <i>vs</i> CTL mice, ^#<i>P</i> ≤ 0,05 <i>vs</i> AA mice, ^##<i>P</i> ≤ 0,01 <i>vs</i> AA mice and ^###<i>P</i> ≤ 0,001 <i>vs</i> AA mice.</p