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Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system.

ABSTRACT: The mechanisms of nephroprotection in nondiabetic chronic kidney disease (CKD) models by sodium-glucose cotransporter 2 (SGLT2) inhibitors are not well defined. Five groups were established: sham-operated rats, placebo-treated rats with 5/6 nephrectomy (5/6Nx), 5/6Nx + telmisartan (5 mg/kg/day), 5/6Nx + empagliflozin (3 mg/kg/day), and 5/6Nx + empagliflozin (15 mg/kg/day). Treatment duration was 95 days. Empagliflozin showed a dose-dependent beneficial effect on the change from baseline of creatinine clearance (Ccr). The urinary albumin-to-creatinine ratio likewise improved in a dose-dependent manner. Both dosages of empagliflozin improved morphological kidney damage parameters such as renal interstitial fibrosis and glomerulosclerosis. 5/6 nephrectomy led to a substantial reduction of urinary adenosine excretion, a surrogate parameter of the tubuloglomerular feedback (TGF) mechanism. Empagliflozin caused a dose-dependent increase in urinary adenosine excretion. The urinary adenosine excretion was negatively correlated with renal interstitial fibrosis and positively correlated with Ccr. Immunofluorescence analysis revealed that empagliflozin had no effect on CD8⁺ and CD4⁺ T cells as well as on CD68⁺ cells (macrophages). To further explore potential mechanisms, a nonhypothesis-driven approach was used. RNA sequencing followed by quantitative real-time polymerase chain reaction revealed that complement component 1Q subcomponent A chain (C1QA) as well as complement component 1Q subcomponent C chain (C1QC) gene expression were upregulated in the placebo-treated 5/6Nx rats and this upregulation was blunted by treatment with empagliflozin. In conclusion, empagliflozin-mediated nephroprotection in nondiabetic CKD is due to a dose-dependent activation of the TGF as well as empagliflozin-mediated effects on the complement system.

SUBMITTER: Chen X

PROVIDER: S-EPMC10085567 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system.

Chen Xin X Delić Denis D Cao Yaochen Y Shen Linghong L Shao Qin Q Zhang Zheyu Z Wu Hongwei H Hasan Ahmed A AA Reichetzeder Christoph C Gaballa Mohamed M S MMS Krämer Bernhard K BK Klein Thomas T Yin Lianghong L He Ben B Morgera Stanislao S Hocher Berthold B

American journal of physiology. Cell physiology 20230213 4

The mechanisms of nephroprotection in nondiabetic chronic kidney disease (CKD) models by sodium-glucose cotransporter 2 (SGLT2) inhibitors are not well defined. Five groups were established: sham-operated rats, placebo-treated rats with 5/6 nephrectomy (5/6Nx), 5/6Nx + telmisartan (5 mg/kg/day), 5/6Nx + empagliflozin (3 mg/kg/day), and 5/6Nx + empagliflozin (15 mg/kg/day). Treatment duration was 95 days. Empagliflozin showed a dose-dependent beneficial effect on the change from baseline of creat ...[more]

PMID: 36779666

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Project description:Study objectivesTo better understand the sometimes catastrophic effects of sleep loss on naturalistic decision making, we investigated effects of sleep deprivation on decision making in a reversal learning paradigm requiring acquisition and updating of information based on outcome feedback.DesignSubjects were randomized to a sleep deprivation or control condition, with performance testing at baseline, after 2 nights of total sleep deprivation (or rested control), and following 2 nights of recovery sleep. Subjects performed a decision task involving initial learning of go and no go response sets followed by unannounced reversal of contingencies, requiring use of outcome feedback for decisions. A working memory scanning task and psychomotor vigilance test were also administered.SettingSix consecutive days and nights in a controlled laboratory environment with continuous behavioral monitoring.SubjectsTwenty-six subjects (22-40 y of age; 10 women).InterventionsThirteen subjects were randomized to a 62-h total sleep deprivation condition; the others were controls.Measurements and resultsUnlike controls, sleep deprived subjects had difficulty with initial learning of go and no go stimuli sets and had profound impairment adapting to reversal. Skin conductance responses to outcome feedback were diminished, indicating blunted affective reactions to feedback accompanying sleep deprivation. Working memory scanning performance was not significantly affected by sleep deprivation. And although sleep deprived subjects showed expected attentional lapses, these could not account for impairments in reversal learning decision making.ConclusionsSleep deprivation is particularly problematic for decision making involving uncertainty and unexpected change. Blunted reactions to feedback while sleep deprived underlie failures to adapt to uncertainty and changing contingencies. Thus, an error may register, but with diminished effect because of reduced affective valence of the feedback or because the feedback is not cognitively bound with the choice. This has important implications for understanding and managing sleep loss-induced cognitive impairment in emergency response, disaster management, military operations, and other dynamic real-world settings with uncertain outcomes and imperfect information.

Dataset Information

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system.

Publications

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system.

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