Chronic interstitial fibrosis in the rat kidney induced by long-term (6-mo) exposure to lithium

Walker, Robert; Leader, John P.; Bedford, Jennifer J.; Gobé, Glenda C.; Davis, Gerard; Vos, Frederiek E.; deJong, Sylvia; Schollum, John

doi:10.1152/ajprenal.00182.2012

Cited by 36 publications

(47 citation statements)

References 32 publications

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“…Kidney damage in humans and rodents chronically treated with lithium is mostly characterized by proximal tubular atrophy and chronic interstitial fibrosis (Table 1). [69][70][71][72] Some lithium-treated patients also display glomerulosclerosis, but animal studies revealed that this pathology occurs after the onset of interstitial fibrosis and tubular atrophy. 7,69,[72][73][74][75] Although this suggests that glomerulosclerosis results from damage at other renal segments, it probably constitutes an essential step in the final progression to ESRD.…”

Section: Esrdmentioning

confidence: 99%

“…[69][70][71][72] Some lithium-treated patients also display glomerulosclerosis, but animal studies revealed that this pathology occurs after the onset of interstitial fibrosis and tubular atrophy. 7,69,[72][73][74][75] Although this suggests that glomerulosclerosis results from damage at other renal segments, it probably constitutes an essential step in the final progression to ESRD. 76 Other than these pathologic features, histology on biopsies or magnetic resonance imaging scans revealed that a number of lithium-treated patients also displays renal microcysts.…”

Section: Esrdmentioning

confidence: 99%

“…76,79,80 In agreement with these findings, the expression of TGF-b1 is enhanced in collecting ducts of lithium-treated rats. 69 Elevated b-catenin levels in principal cells might also contribute to the fibrosis, because Dickkopf-1, an antagonist of canonical Wnt signaling, and ICG-001, which disrupts b-catenin-mediated gene transcription, strongly reduced interstitial fibrosis in mouse nephropathy models. 81,82 As pointed out, lithium can easily enter proximal tubule cells, and a recent study showed that, several days after a single lithium dose, which was below or similar to therapeutic amounts given to patients with bipolar disorder, the proximal tubule exhibited an enhanced expression of different proproliferative proteins.…”

Section: Esrdmentioning

confidence: 99%

See 2 more Smart Citations

Lithium in the Kidney: Friend and Foe?

Alsady

Baumgarten²,

Deen

et al. 2015

JASN

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Trace amounts of lithium are essential for our physical and mental health, and administration of lithium has improved the quality of life of millions of patients with bipolar disorder for .60 years. However, in a substantial number of patients with bipolar disorder, long-term lithium therapy comes at the cost of severe renal side effects, including nephrogenic diabetes insipidus and rarely, ESRD. Although the mechanisms underlying the lithium-induced renal pathologies are becoming clearer, several recent animal studies revealed that short-term administration of lower amounts of lithium prevents different forms of experimental AKI. In this review, we discuss the knowledge of the pathologic and therapeutic effects of lithium in the kidney. Furthermore, we discuss the underlying mechanisms of these seemingly paradoxical effects of lithium, in which fine-tuned regulation of glycogen synthase kinase type 3, a prime target for lithium, seems to be key. The new discoveries regarding the protective effect of lithium against AKI in rodents call for follow-up studies in humans and suggest that long-term therapy with low lithium concentrations could be beneficial in CKD.

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Section: Esrdmentioning

confidence: 99%

Section: Esrdmentioning

confidence: 99%

Section: Esrdmentioning

confidence: 99%

See 1 more Smart Citation

Lithium in the Kidney: Friend and Foe?

Alsady

Baumgarten²,

Deen

et al. 2015

JASN

View full text Add to dashboard Cite

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“…[30][31][32] The consequences of such a prolonged G2 cell cycle arrest are not fully understood, although recent investigations of different AKI models indicate that activation of c-Jun NH 2 -terminal signaling in G2-arrested cells can lead to renal fibrosis due to the upregulation of profibrotic cytokines, including TGF-b1. 24 Because fibrosis and CKD are also observed after long-term lithium treatment, 33 and lithium has been shown to activate c-Jun NH 2 -terminal signaling 16 and stimulate TGF-b1 production in the collecting duct, 33 the role of G2-arrested cells in lithium-induced fibrosis should be further investigated.…”

Section: Lithium Enhances G1/s Cell Cycle Progressionmentioning

confidence: 99%

Lithium Causes G2 Arrest of Renal Principal Cells

Groot

Alsady

Jaklofsky

et al. 2014

Journal of the American Society of Nephrology

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Vasopressin-regulated expression and insertion of aquaporin-2 channels in the luminal membrane of renal principal cells is essential for urine concentration. Lithium affects urine concentrating ability, and approximately 20% of patients treated with lithium develop nephrogenic diabetes insipidus (NDI), a disorder characterized by polyuria and polydipsia. Lithium-induced NDI is caused by aquaporin-2 downregulation and a reduced ratio of principal/intercalated cells, yet lithium induces principal cell proliferation. Here, we studied how lithium-induced principal cell proliferation can lead to a reduced ratio of principal/intercalated cells using two-dimensional and three-dimensional polarized cultures of mouse renal collecting duct cells and mice treated with clinically relevant lithium concentrations. DNA image cytometry and immunoblotting revealed that lithium initiated proliferation of mouse renal collecting duct cells but also increased the G2/S ratio, indicating G2/M phase arrest. In mice, treatment with lithium for 4, 7, 10, or 13 days led to features of NDI and an increase in the number of principal cells expressing PCNA in the papilla. Remarkably, 30%-40% of the PCNA-positive principal cells also expressed pHistone-H3, a late G2/M phase marker detected in approximately 20% of cells during undisturbed proliferation. Our data reveal that lithium treatment initiates proliferation of renal principal cells but that a significant percentage of these cells are arrested in the late G2 phase, which explains the reduced principal/intercalated cell ratio and may identify the molecular pathway underlying the development of lithium-induced renal fibrosis.

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“…There are about 10% of the general adult population affected by CRF worldwide, which is often complicated by sepsis and cardiovascular disease [4]. Previous study has revealed that CRF is characterized by slowly progressive chronic renal interstitial fibrosis (RIF) and accompanied with increased oxidative stress (OS) that is already found in the early stage of renal disease [5]. Although a low protein diets is the effective treatment regimen for CRF, the side effects of this strategy cannot be ignored, such as a probable occurrence of proteinuria and functional impairment [6].…”

Section: Introductionmentioning

confidence: 99%

Effects of Long Non-Coding RNA LINC00963 on Renal Interstitial Fibrosis and Oxidative Stress of Rats with Chronic Renal Failure via the Foxo Signaling Pathway

Chen

Zhang

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Chronic renal failure (CRF) is usually associated with chronic diseases such as congestive heart failure and diabetes mellitus, the prevalence of which is increased with age. This study is designed to investigate the role of long intergenic non-coding RNA (lincRNA) LINC00963 in renal interstitial fibrosis (RIF) and oxidative stress (OS) of CRF via the forkhead box O (FoxO) signaling pathway. Methods: Microarray data and annotated probe files related to CRF were downloaded by retrieving Gene Expression Omnibus (GEO) database to screen differentially expressed lncRNA. Multi Experiment Matrix (MEM) website and dual-luciferase reporter gene assay were used to predict and verify the target gene of LINC00963, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to identify the major signaling pathways involved. A total of 60 Wistar male rats were randomly selected and divided into the sham (n = 10) and model (n = 50) groups. Five rats in the sham group and thirty rats in the model group were sub-categorized into the control, blank, negative control (NC), LINC00963 vector, si-LINC00963, si-FoxO3, and si-LINC00963 + si-FoxO3 groups (n = 5). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were performed to evaluate the expressions of LINC00963, FoxO3a, TGF-β1, FN, GSH-PX, Bax, and Bcl-2. Measurement of changes in OS indexes including BUN, MDA, GSH-Px, SOD, and Na⁺-K⁺-ATP were conducted. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of inflammatory factors including TNF-α, IL-6, ICAM-1 and FN. TUNEL staining was performed to evaluate cell apoptosis. Results: LINC00963 was highly expressed in CRF rats and FoxO3 was predicted and then verified as a target gene of LINC00963. FoxO3 gene participated in the FOXO signaling pathway. Compared with the blank and NC groups, there were significantly decreased expressions of LINC00963, TGF-β1, FN, and Bax in the si-LINC00963 group, while increased expressions of GSH-PX, FoxO3a, and Bcl-2. The vitality values of BUN and MDA in the si-LINC00963 group declined, while enzymatic activities of GSH-Px, SOD and Na⁺-K⁺-ATP elevated in comparison to the blank and NC groups. The levels of TNF-α, IL-6, ICAM-1 and FN, and cell apoptosis rate in the si-LINC00963 group decreased in comparison to the blank and NC groups. All the results in the si-LINC00963 group were opposite in the LINC00963 vector and si-FoxO3 groups. Conclusion: Taken together, we conclude that down-regulation of LINC00963 suppresses RIF and OS of CRF by activating the FoxO signaling pathway.

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Chronic interstitial fibrosis in the rat kidney induced by long-term (6-mo) exposure to lithium

Cited by 36 publications

References 32 publications

Lithium in the Kidney: Friend and Foe?

Lithium in the Kidney: Friend and Foe?

Lithium Causes G2 Arrest of Renal Principal Cells

Effects of Long Non-Coding RNA LINC00963 on Renal Interstitial Fibrosis and Oxidative Stress of Rats with Chronic Renal Failure via the Foxo Signaling Pathway

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