Autosomic dominant polycystic kidney disease and metformin: Old knowledge and new insights on retarding progression of chronic kidney disease

Casarella, Alessandro; Nicotera, Ramona; Zicarelli, Maria Teresa; Urso, Alessandra; Presta, Pierangela; Deodato, Francesca; Bolignano, Davide; Sarro, Giovambattista De; Andreucci, Michele; Russo, Emilio; Coppolino, Giuseppe

doi:10.1002/med.21850

Cited by 10 publications

(5 citation statements)

References 41 publications

(89 reference statements)

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“…Specifically, this reduced cAMP excretion generally correlated with metformin-dependent improvements in the cystic index, total kidney weight-to-body weight ratio, and improved GFR. Moreover, elevated ERK1/2 signaling is believed to promote cystogenesis and is a likely consequence of elevated cellular cAMP generation (70). Consistent with the idea that metformin reduces disease severity at least in part via this signaling pathway, we observed significant decreases in the ratios of active, phosphorylated ERK1/2 to total ERK1/2 in kidney immunoblots from 12-mo-old female and 9-mo-old male mice, along with downward trends in 12-mo-old male and 9-mo-old female mice, with metformin treatment relative to untreated controls (see Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Metformin improves relevant disease parameters in an autosomal dominant polycystic kidney disease mouse model

Pastor-Soler

Pham

et al. 2022

American Journal of Physiology-Renal Physiology

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Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the PKD1 or PKD2 genes encoding polycystins, presents with progressive development of kidney cysts and eventual end-stage kidney disease (ESKD) with limited treatment options. Previous work showed that metformin reduces cyst growth in rapid ADPKD mouse models via inhibition of CFTR-mediated fluid secretion, mTOR, and cAMP pathways. The present study importantly tested the effectiveness of metformin as a therapy for ADPKD in a more clinically relevant Pkd1RC/RC mouse model, homozygous for the R3277C knock-in point mutation in the Pkd1 gene. This mutation causes ADPKD in humans. Pkd1RC/RC male and female mice, which have slow progression to ESKD, received metformin (300 mg/kg/day in drinking water vs. water alone) from 3 to 9 or 12 months of age. As previously reported, Pkd1RC/RC females had a more severe disease phenotype than males. Metformin treatment reduced the ratio of total kidney weight to body weight relative to age- and sex-matched untreated controls at both 9 and 12 months and reduced cystic index in females at 9 months. Metformin also increased glomerular filtration rate (GFR), lowered systolic blood pressure, improved anemia, and lowered blood urea nitrogen levels relative to controls in both sexes. Moreover, metformin reduced gene expression of key inflammatory markers and both gene and protein expression of kidney injury marker-1 and cyclin-dependent kinase-1 vs. untreated controls. Altogether, these findings suggest several beneficial effects of metformin in this highly relevant slowly progressive ADPKD mouse model, which may help inform new ADPKD therapies in patients.

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Section: Discussionmentioning

confidence: 99%

Metformin improves relevant disease parameters in an autosomal dominant polycystic kidney disease mouse model

Pastor-Soler

Pham

et al. 2022

American Journal of Physiology-Renal Physiology

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“…Autosomal dominant polycystic kidney disease (ADPKD), the most common congenital kidney disorder, is commonly accompanied by abnormal activity of JAK-STAT pathways. 344 , 345 Forced STAT5 expression in ADPKD causes aberrant proliferation by transcriptionally upregulating cyclin D1 in a growth hormone-dependent manner. Pkd1 nl/nl murine models revealed heterotopic JAK2 expression in cyst-lining cells and interstitium and validated that JAK2 inhibition could postpone cystic growth in ADPKD.…”

Section: The Jak-stat Pathway and Diseasesmentioning

confidence: 99%

Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Xue

Yao

et al. 2023

Sig Transduct Target Ther

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The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism of transmembrane signal transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, and other specific molecules activate JAK-STAT signaling to drive a series of physiological and pathological processes, including proliferation, metabolism, immune response, inflammation, and malignancy. Dysregulated JAK-STAT signaling and related genetic mutations are strongly associated with immune activation and cancer progression. Insights into the structures and functions of the JAK-STAT pathway have led to the development and approval of diverse drugs for the clinical treatment of diseases. Currently, drugs have been developed to mainly target the JAK-STAT pathway and are commonly divided into three subtypes: cytokine or receptor antibodies, JAK inhibitors, and STAT inhibitors. And novel agents also continue to be developed and tested in preclinical and clinical studies. The effectiveness and safety of each kind of drug also warrant further scientific trials before put into being clinical applications. Here, we review the current understanding of the fundamental composition and function of the JAK-STAT signaling pathway. We also discuss advancements in the understanding of JAK-STAT–related pathogenic mechanisms; targeted JAK-STAT therapies for various diseases, especially immune disorders, and cancers; newly developed JAK inhibitors; and current challenges and directions in the field.

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“…Cyclic adenosine monophosphate (cAMP) is known to mediate cell proliferation and fluid secretion of renal cystic epithelia in PKD [ 50 ]. In the CKO mouse, the administration of a pharmacological inhibitor of the cAMP response element binding protein (CREB) and a dominant-negative inhibitor of CREB suppressed renal cystic area expansion [ 51 ].…”

Section: Genetically Modified Modelsmentioning

confidence: 99%

Review of the Use of Animal Models of Human Polycystic Kidney Disease for the Evaluation of Experimental Therapeutic Modalities

Nagao

Yamaguchi

2023

JCM

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Autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, and nephronophthisis are hereditary disorders with the occurrence of numerous cysts in both kidneys, often causing chronic and end-stage renal failure. Animal models have played an important role in recent advances in research not only on disease onset and progressive mechanisms but also on the development of therapeutic interventions. For a long time, spontaneous animal models have been used as the primary focus for human diseases; however, after the identification of the nucleotide sequence of the responsible genes, PKD1, PKD2, PKHD1, and NPHPs, various types of genetically modified models were developed by genetic and reproductive engineering techniques and played the leading role in the research field. In this review, we present murine models of hereditary renal cystic diseases, discussing their potential benefits in the development of therapeutic strategies.

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Autosomic dominant polycystic kidney disease and metformin: Old knowledge and new insights on retarding progression of chronic kidney disease

Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common congenital kidney disorder, generally caused by mutations in the PKD1 and PKD2 genes, coding for polycystins 1 and 2. Its pathogenesis is accompanied by

Cited by 10 publications

References 41 publications

Metformin improves relevant disease parameters in an autosomal dominant polycystic kidney disease mouse model

Metformin improves relevant disease parameters in an autosomal dominant polycystic kidney disease mouse model

Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Review of the Use of Animal Models of Human Polycystic Kidney Disease for the Evaluation of Experimental Therapeutic Modalities

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