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The effect of mycophenolate mofetil on podocytes in nephrotoxic serum nephritis.

ABSTRACT: Mycophenolate mofetil (MMF) is applied in proteinuric kidney diseases, but the exact mechanism of its effect on podocytes is still unknown. Our previous in vitro experiments suggested that MMF can ameliorate podocyte damage via restoration of the Ca²⁺-actin cytoskeleton axis. The goal of this study was to characterize podocyte biology during MMF treatment in nephrotoxic serum (NTS) nephritis (NTN). NTN was induced in three-week old wild-type mice. On day 3, half of the mice were treated with MMF (100 mg/kgBW/d p.o.) for one week. On day 10, we performed proteomic analysis of glomeruli as well as super-resolution imaging of the slit diaphragm. For multiphoton imaging of Ca²⁺ concentration ([Ca²⁺]_i), the experimental design was repeated in mice expressing podocyte-specific Ca²⁺ sensor. MMF ameliorated the proteinuria and crescent formation induced by NTS. We identified significant changes in the abundance of proteins involved in Ca²⁺ signaling and actin cytoskeleton regulation, which was further confirmed by direct [Ca²⁺]_i imaging in podocytes showing decreased Ca²⁺ levels after MMF treatment. This was associated with a tendency to restoration of podocyte foot process structure. Here, we provide evidence that MPA has a substantial direct effect on podocytes. MMF contributes to improvement of [Ca²⁺]_i and amelioration of the disorganized actin cytoskeleton in podocytes. These data extend the knowledge of direct effects of immunosuppressants on podocytes that may contribute to a more effective treatment of proteinuric glomerulopathies with the least possible side effects.

SUBMITTER: Hackl A

PROVIDER: S-EPMC10465485 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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The effect of mycophenolate mofetil on podocytes in nephrotoxic serum nephritis.

Hackl A A Nüsken E E Voggel J J Abo Zed S E D SED Binz-Lotter J J Unnersjö-Jess D D Müller C C Fink G G Bohl K K Wiesner E E Diefenhardt P P Dafinger C C Chen H H Wohlfarth M M Müller R-U RU Hackl M J MJ Schermer B B Nüsken K-D KD Weber L T LT

Scientific reports 20230829 1

Mycophenolate mofetil (MMF) is applied in proteinuric kidney diseases, but the exact mechanism of its effect on podocytes is still unknown. Our previous in vitro experiments suggested that MMF can ameliorate podocyte damage via restoration of the Ca<sup>2+</sup>-actin cytoskeleton axis. The goal of this study was to characterize podocyte biology during MMF treatment in nephrotoxic serum (NTS) nephritis (NTN). NTN was induced in three-week old wild-type mice. On day 3, half of the mice were treat ...[more]

PMID: 37644089

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Project description:Mycophenolate mofetil (MMF) is an immunosuppressant drug being used for induction and maintenance of remission of lupus nephritis in systemic lupus erythematosus. Evidence about its use was sought from full publications and abstracts of randomised trials and cohort studies by using a variety of search strategies. Efficacy and adverse event outcomes were sought. Five randomised trials enrolled patients with World Health Organization (WHO) class III, IV, or V (mostly IV) lupus nephritis, predominantly comparing MMF (1 to 3 g daily) with cyclophosphamide and steroid. Complete response and complete or partial response was significantly more frequent with MMF than with cyclophosphamide, with numbers needed to treat of 8 (95% confidence interval 4.3 to 60) to induce one additional complete or partial response, with wide confidence intervals. Death was reported less frequently with MMF (0.7%, 1 death in 152 patients) than with cyclophosphamide (7.8%, 12 deaths in 154 patients), with a number needed to treat to prevent (NNTp) one death of 14 (8 to 48). Hospital admission was also lower with MMF (1.7% versus 15%; NNTp 7.4 [4.8 to 16]). Serious infections, leucopaenia, amenorrhoea, and hair loss were all significantly less frequent with MMF than with cyclophosphamide, but diarrhoea was significantly more common with MMF. Ten of 18 cohort studies enrolled only patients with lupus nephritis (author-defined or WHO class III to V). Seven of these 10 reported that complete or partial response with MMF (mostly 1 or 2 g daily) with steroid occurred in 121/151 (80%) and that treatment failure or no response occurred in 30/151 (20%). Adverse events were generally similar in cohort studies with and without only patients with lupus nephritis. In all 18 cohorts, gastrointestinal adverse events (diarrhoea, nausea, vomiting) occurred in 30%, infection in 23%, and serious infection in 4.3%. Adverse event discontinuations occurred in 14% and lack of efficacy occurred in 10%. There was a single death with MMF, a mortality rate over the course of 1 year of approximately 0.2%. The results form a basis on which to plan future studies and provide a guide for the use of MMF in lupus nephritis until results of larger studies are available. At least one such study is under way.

Dataset Information

The effect of mycophenolate mofetil on podocytes in nephrotoxic serum nephritis.

Publications

The effect of mycophenolate mofetil on podocytes in nephrotoxic serum nephritis.

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