Mesenchymal Stromal Cells Induce Podocyte Protection in the Puromycin Injury Model

Abstract

Podocytes are specialized cells with a limited capacity for cell division that do not regenerate in response to injury and loss. Insults that compromise the integrity of podocytes promote proteinuria and progressive renal disease. The aim of this study was to evaluate the potential renoprotective and regenerative effects of mesenchymal stromal cells (mSC) in a severe form of the podocyte injury model induced by intraperitoneal administration of puromycin, aggravated by unilateral nephrectomy. Bone derived mSC were isolated and characterized according to flow cytometry analyses and to their capacity to differentiate into mesenchymal lineages. Wistar rats were divided into three groups: Control, PAN, and PAN+ mSC, consisting of PAN rats treated with 2 × 105 mSC. PAN rats developed heavy proteinuria, hypertension, glomerulosclerosis and significant effacement of the foot process. After 60 days, PAN rats treated with mSC presented a significant amelioration of all these abnormalities. In addition, mSC treatment recovered WT1 expression, improved nephrin, podocin, synaptopodin, podocalyxin, and VEGF expression, and downregulated proinflammatory Th1 cytokines in the kidney with a shift towards regulatory Th2 cytokines. In conclusion, mSC administration induced protection of podocytes in this experimental PAN model, providing new perspectives for the treatment of renal diseases associated with podocyte damage.

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“…The positive effects of ASCs administration in reducing proteinuria levels are possibly due to direct effects on the glomerular filtration barrier, particularly on the structural and functional integrity of podocytes. We have recently reported renoprotective effects of MSC in a podocytopathy model induced by puromycin aminonucleoside recovering WT1 expression, ameliorating podocyte slit diaphragm and cytoskeletal proteins, such as nephrin and podocin synaptopodin and podocalyxin [25]. Similar results using BM-MSC in diabetic mice were reported by Wang and coworkers [26].…”

“…In addition, tubular function was also improved in animals treated with ASCs, as measured by the fractional excretion of sodium and fractional excretion of potassium. We have previously described renoprotective effects of BM-MSCs treatment in the rat remnant kidney model and in the puromycin model [15,25]. These effects were also described in models of experimental glomerulonephritis [27] and renal transplantation [28] treated with BM-MSC and sepsisinduced kidney injury, treated with human wharton's jelly-derived MSC [29].…”

Eicosapentaenoic acid reduces inflammation and apoptosis by SREBP1/TLR4/MYD88

“…Recently, dysfunction of podocytes is identifi ed as the pathogenesis of DN, might participate in the early stages of this disease (14,15). The cytoskeletal pro tein (synaptopodin) and the slit diaphragm (podocin) are performed to the functional and structural integrity of podocytes (16). High glucose-induced low expression of podocin and synaptopodin was dramatically enhanced by EPA administration, which may indicate that EPA can affect the function of podocyte.…”

Therapeutic potential of mesenchymal stem cells in multiple organs affected by COVID-19

“…MSCs promoted accelerated M2-polarized macrophage infiltration, trophic factors secretion, tubular epithelium proliferation, renal function improvement and IL-6 and TNFα reduction in mice with rhabdomyolysis-induced AKI [ 152 ]. Other studies also reported that MSCs promoted an increased expression of IL-10 and IL-4 mRNA, decreased expression of IL-1β and TNF-α mRNA, and decreased inflammatory cells infiltration, reduced a proinflammatory (Th1) environment, and increased anti-inflammatory effects (Th2) [ 147 , 153 , 154 ].…”

“…MSC transplantation into the renal subcapsular region of rats with podocyte injury induced by puromycin promoted blood pressure reduction and decreased proteinuria, albuminuria, and serum creatinine. Renal regenerative and reparative effects of MSCs are also related to restoration of Wilms' tumor suppressor 1 (WT1) and VEGF expression and improvement of podocytes' functional and structural integrity, including proteins such as nephrin and podocin (slit diaphragm), synaptopodin, and podocalyxin (cytoskeletal proteins) [ 154 ]. Marrow mononuclear cell fraction, that includes MSC and other progenitor cells, can also promote renal tissue restoration [ 155 ].…”