Nephropathic Cystinosis: Pathogenic Roles of Inflammation and Potential for New Therapies

Elmonem, Mohamed A.; Veys, Koenraad; Prencipe, Giusi

doi:10.3390/cells11020190

Cited by 11 publications

(7 citation statements)

References 88 publications

(124 reference statements)

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“…In conclusion, our data add to the growing body of evidence demonstrating a role for inflammation in the development and progression of kidney disease in cystinosis ( 38 ). The activation of multiple inflammatory pathways and their interplay with other mechanisms involved in the pathogenesis of cystinosis, including increased oxidative stress, autophagy, mechanisms of cell death, and tissue fibrosis, have been reported ( 15 – 17 , 19 ).…”

Section: Discussionsupporting

confidence: 71%

Nlrp2 deletion ameliorates kidney damage in a mouse model of cystinosis

Rossi,

Matteo,

Diomedi-Camassei

et al. 2024

Front. Immunol.

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Cystinosis is a rare autosomal recessive disorder caused by mutations in the CTNS gene that encodes cystinosin, a ubiquitous lysosomal cystine/H+ antiporter. The hallmark of the disease is progressive accumulation of cystine and cystine crystals in virtually all tissues. At the kidney level, human cystinosis is characterized by the development of renal Fanconi syndrome and progressive glomerular and interstitial damage leading to end-stage kidney disease in the second or third decade of life. The exact molecular mechanisms involved in the pathogenesis of renal disease in cystinosis are incompletely elucidated. We have previously shown upregulation of NLRP2 in human cystinotic proximal tubular epithelial cells and its role in promoting inflammatory and profibrotic responses. Herein, we have investigated the role of NLRP2 in vivo using a mouse model of cystinosis in which we have confirmed upregulation of Nlrp2 in the renal parenchyma. Our studies show that double knock out Ctns-/- Nlrp2-/- animals exhibit delayed development of Fanconi syndrome and kidney tissue damage. Specifically, we observed at 4-6 months of age that animals had less glucosuria and calciuria and markedly preserved renal tissue, as assessed by significantly lower levels of inflammatory cell infiltration, tubular atrophy, and interstitial fibrosis. Also, the mRNA expression of some inflammatory mediators (Cxcl1 and Saa1) and the rate of apoptosis were significantly decreased in 4-6-month old kidneys harvested from Ctns-/- Nlrp2-/- mice compared to those obtained from Ctns-/-mice. At 12-14 months of age, renal histological was markedly altered in both genetic models, although double KO animals had lower degree of polyuria and low molecular weight proteinuria and decreased mRNA expression levels of Il6 and Mcp1. Altogether, these data indicate that Nlrp2 is a potential pharmacological target for delaying progression of kidney disease in cystinosis.

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Section: Discussionsupporting

confidence: 71%

Nlrp2 deletion ameliorates kidney damage in a mouse model of cystinosis

Rossi,

Matteo,

Diomedi-Camassei

et al. 2024

Front. Immunol.

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“…Cysteamine is a thiol-containing compound used in the treatment of cystinosis by increasing the intracellular level of glutathione 10 11 . Studies have linked the therapeutic use of cysteamine against cystinosis with its anti-apoptotic effect 12 13 . Anti-malarial effect of cysteamine was also revealed by study of Moradin et al, 14 , and its oxidized derivative was shown to suppress sickling in sickle cell patients 15 .…”

Section: Introductionmentioning

confidence: 99%

Cysteamine Attenuate Intestinal Reperfusion Injury Induced by Occlusion of Mesenteric Artery by Enhancing Intracellular Thiol Activities

et al. 2022

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Background Ischemia/reperfusion has been reported to further damage the intestine reperfusion injury (IRI) and cause multiple distal organ dysfunction through oxidative stress, inflammation, and apoptosis. Cysteamine is known to inhibit oxidative stress, inflammatory cytokines and apoptosis. This experiment was designed to evaluate the role of cysteamine against IRI in rats Methods Thirty-two Wistar rat strains were assigned to four groups: sham, Intestinal-reperfusion injury (IRI), 50 mg/kg and 100 mg/kg cysteamine treatment IRI. A 5 cm segment of terminal ileum was twisted 360° clockwise along the mesentery for 45 minutes to induce ischemia before detorsion. Tissues were preserved for biochemical evaluation and histology 4 hours after detorsion. Activities of GPx, GSH, protein and non-protein thiol, H2O2, MDA were evaluated. Serum concentration of nitrite, MPO, ALT, AST TNF-alpha and IL-6 were measured. Caspase 3 and bax were evaluated by immunohistochemistry. Statistical significance was set as p<0.05 Results Significant (p<0.05) increase in H2O2, MDA and nitrite but reduction in GPx, GSH, protein thiol and non-protein thiol in the IRI rats was reversed by 50 and 100 mg/kg cysteamine. Serum MPO, TNF-α, IL6, AST and ALT was significantly elevated in IRI while the rats treated with cysteamine showed a significant decrease (p<0.05) in the activities of these inflammatory and hepatic injury markers. Conclusion Cysteamine mitigate IRI by enhancing intracellular antioxidant defense system, inhibiting inflammatory mediators and intestinal tissue expression of pro-apoptotic protein.

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“…A recent study from Germany showed that starting cysteamine soon after birth yielded almost normal growth and kidney function in these patients with a neonatal diagnosis [ 30 , 31 ]. Still, the availability of such strategies in low-income countries is questionable, let alone access to potential innovative therapies such as stem cell transplantation [ 32 ], or inflammation-targeted therapies [ 33 ], which are very likely to be available only in a restricted number of DEed countries.…”

Section: Discussionmentioning

confidence: 99%

Worldwide disparities in access to treatment and investigations for nephropathic cystinosis: a 2023 perspective

Regnier,

Flammier,

Boutaba

et al. 2023

Pediatr Nephrol

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Background Nephropathic cystinosis (NC) is a rare lysosomal disease, leading to early kidney failure and extra-renal comorbidities. Its prognosis strongly relies on early diagnosis and treatment by cysteamine. Developing economies (DEing) face many challenges when treating patients for rare and chronic diseases. The aim here is to evaluate the access to investigations and treatment in DEing, and to assess for potential inequalities with Developed Economies (DEed). Methods In this international cross-sectional study, a questionnaire on access, price and reimbursement of genetic, biological analyses, and treatment was sent to nephrology centers worldwide during 2022. Results A total of 109 centers responded, coming from 49 countries and managing 741 patients: 43 centers from 30 DEing and Economies in transition (TrE), and 66 from 19 DEed. In 2022, genetics availability was 63% in DEing and 100% in DEed, whereas intra leukocytes cystine levels (IL-CL) were available for 30% of DEing patients, and 94% of DEed patients, both increasing over the last decade, as has access to immediate release cysteamine and to cysteamine eye drops in DEing. However, delayed released cysteamine can be delivered to only 7% vs. 74% of patients from DEing and DEed, respectively, and is still poorly reimbursed in DEing. Conclusions Over the last decade, access to investigations (namely genetics and IL-CL) and to cysteamine have improved in DEing and TrE. However, discrepancies remain with DEed: access to delayed released cysteamine is limited, and reimbursement is still profoundly insufficient, therefore limiting their current use. Graphical abstract

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Nephropathic Cystinosis: Pathogenic Roles of Inflammation and Potential for New Therapies

Cited by 11 publications

References 88 publications

Nlrp2 deletion ameliorates kidney damage in a mouse model of cystinosis

Nlrp2 deletion ameliorates kidney damage in a mouse model of cystinosis

Cysteamine Attenuate Intestinal Reperfusion Injury Induced by Occlusion of Mesenteric Artery by Enhancing Intracellular Thiol Activities

Worldwide disparities in access to treatment and investigations for nephropathic cystinosis: a 2023 perspective

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