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      The role of sirolimus in proteinuria in diabetic nephropathy rats

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          Abstract

          Objective(s):

          The aim of this study was to observe the impact of sirolimus on proteinuria in streptozotocin (STZ) induced diabetic rats.

          Materials and Methods:

          Rats were given a single injection of STZ to induce diabetic rat model. Rats’ 24 hr urine was collected to test, urinary and the kidney tissues were harvested at the 8 th and 20 th weeks, respectively. Podocyte morphological changes were examined by electron microscopy and the ZO-1, podocin expressions in kidneys were detected by immunohistochemistry; the protein levels of Raptor and pS6 were measured by Western blot assay.

          Results:

          In the early stage of diabetic nephropathy (DN), sirolimus reduced the proteinuria significantly ( P<0.05); but in the advanced stage of DN, sirolimus worsened proteinuria ( P<0.05). Electron microscopy test suggested that sirolimus could reduce the injury of podocyte at the early DN, but increased the injury at the late DN podocyte. Immunohistochemistry results indicated that sirolimus increased the expressions of podocin and ZO-1 at the early DN ( P<0.05), but reduced the expressions of ZO-1 and podocin ( P<0.05) at the advanced DN. In the different periods of DN, the expression levels of Raptor and pS6 in sirolimus-treated groups were significantly lower than in the DN control groups ( P<0.05).

          Conclusion:

          Sirolimus can reduce proteinuria and alleviate the early DN podocyte injury in diabetic rat model by inhibiting the activity of mTORC1; but in the advanced stage of DN, sirolimus can increase podocyte injury and urine protein level.

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          Strategies for the management of adverse events associated with mTOR inhibitors.

          Bruce Kaplan, Yasir Qazi, Jason R Wellen (2014)
          Mammalian target of rapamycin (mTOR) inhibitors are used as potent immunosuppressive agents in solid-organ transplant recipients (everolimus and sirolimus) and as antineoplastic therapies for various cancers (eg, advanced renal cell carcinoma; everolimus, temsirolimus, ridaforolimus). Relevant literature, obtained from specific PubMed searches, was reviewed to evaluate the incidence and mechanistic features of specific adverse events (AEs) associated with mTOR inhibitor treatment, and to present strategies to effectively manage these events. The AEs examined in this review include stomatitis and other cutaneous AEs, wound-healing complications (eg, lymphocele, incisional hernia), diabetes/hyperglycemia, dyslipidemia, proteinuria, nephrotoxicity, delayed graft function, pneumonitis, anemia, hypertension, gonadal dysfunction, and ovarian toxicity. Strategies for selecting appropriate patients for mTOR inhibitor therapy and minimizing the risks of AEs are discussed, along with best practices for identifying and managing side effects. mTOR inhibitors are promising therapeutic options in immunosuppression and oncology; most AEs can be effectively detected and managed or reversed with careful monitoring and appropriate interventions.
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            Podocin localizes in the kidney to the slit diaphragm area.

            Séverine Roselli, Olivier Gribouval, Nicolas Boute … (2002)
            We recently cloned a novel gene, NPHS2, involved in autosomal recessive steroid-resistant nephrotic syndrome. This gene encodes a novel podocyte protein, podocin. Given its similarity with the stomatin family proteins, podocin is predicted to be an integral membrane protein with a single membrane domain forming a hairpin-like structure placing both N- and C-termini in the cytosol. Here, we show by in situ hybridization, that during development, the NPHS2 transcript is first expressed in mesonephric podocytes from the S-shaped body and, later, in the metanephric kidney, in the future podocytes at the late S-shaped body stage. In the mature kidney, NPHS2 is exclusively expressed in the podocytes of mature glomeruli. We generated rabbit polyclonal antibodies against fusion proteins derived from the N- and the C-terminal regions of podocin which detected a single band of 49-kd in transfected HEK293 cell lysates by immunoprecipitation and Western blotting. By immunohistology, podocin was detected in podocytes from the early capillary loop stage in the developing nephrons, and at the basal pole, along the GBM, in mature glomeruli. By electron microscopy, we demonstrate that podocin is facing the slit diaphragm with its two ends in the cytoplasm of the foot processes, in agreement with its predicted structure. Our results suggest that podocin could serve to anchor directly or indirectly components of the slit diaphragm to the cytoskeleton.
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              Efficacy on renal function of early conversion from cyclosporine to sirolimus 3 months after renal transplantation: concept study.

              A.-E. Heng, JoAnn M. Thierry, O. Toupance … (2009)
              Sirolimus (SRL) allows to minimize the use of cyclosporine (CsA), but de novo administration after transplantation is associated with various complications. We report a prospective, open-label, multicenter randomized study to evaluate conversion from a CsA-based regimen to a SRL-based regimen 3 months after transplantation. One hundred ninety-two of a total of 237 patients were eligible at 3 months to be converted to SRL (n = 95) or to continue CsA (n = 97). All patients were also given mycophenolate mofetil (MMF) and oral steroids, planned to be discontinued at month 8. The primary endpoint, the clearance estimated according to Cockcroft and Gault at week 52, was significantly better in the SRL group (68.9 vs. 64.4 mL/min, p = 0.017). Patient and graft survival were not statistically different. The incidence of acute rejection episodes, mainly occurring after withdrawal of steroids, was numerically but not statistically higher in the SRL group (17% vs. 8%, p = 0.071). Sixteen patients discontinued SRL, mainly for adverse events (n = 11), and seven patients discontinued CsA for renal failure or acute rejection. Significantly, more patients in the SRL group reported aphthous, diarrhea, acne and high triglyceride levels. Conversion CsA to SRL 3 months after transplantation combined with MMF is associated with improvement in renal function.
              Article 0 comments Cited 56 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Iran J Basic Med Sci
                Journal ID (iso-abbrev): Iran J Basic Med Sci
                Title: Iranian Journal of Basic Medical Sciences
                Publisher: Mashhad University of Medical Sciences (Iran )
                ISSN (Print): 2008-3866
                ISSN (Electronic): 2008-3874
                Publication date (Print): December 2017
                Volume: 20
                Issue: 12
                Pages: 1339-1344
                Affiliations
                [1 ]Department of Transplantation, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
                Author notes
                [* ] Corresponding author: Cai Yong. Department of Transplantation, the First Affiliated Hospital of Wenzhou Medical University. Tel: 86-577-55579473; Fax: 86-577-88069555; email: yorkcai@ 123456126.com
                Article
                Publisher ID: IJBMS-20-1339
                DOI: 10.22038/IJBMS.2017.9618
                PMC ID: 5722994
                SO-VID: cb83680d-be24-49a1-841d-c3aa66ca894d
                Copyright © Copyright: © Iranian Journal of Basic Medical Sciences
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 16 March 2017
                Date accepted : 28 September 2017
                Categories
                Subject: Original Article

                Keywords: diabetic nephropathies,mtor protein,podocytes,proteinuria,sirolimus
                Data availability:
                Keywords: diabetic nephropathies, mtor protein, podocytes, proteinuria, sirolimus

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