CONICET | Buscador de Institutos y Recursos Humanos

The most detrimental complication of diabetes mellitus (DM) is diabetic nephropathy (DN), a clinical syndrome comprised of kidney damage and increased risk for cardiovascular disease. DN is associates with functional and histological changes that include: albuminuria, mesangial expansion, glomerulosclerosis and tubuloinsterstitial fibrosis. Until now, there is no cure to DN; patient`s management comprises the use of drugs to control hyperglycemia and blood pressure. If required, hemodialysis is prescribed. Unfortunately, these treatments only help to slow DN progression. The progression of DN, secondary to type 1 DM (T1DM) or type 2 DM (T2DM), follows the same pathophysiological sequence. Nevertheless, in general the patients with T2DM have additional risk factors which exacerbate renal damage (hypertension, obesity, dyslipidemia and renal ischemic disease provoked by arteriosclerosis), making the management of this cases more complex than ND derived from T1DM. Multipotent mesenchymal stromal cells also referred as mesenchymal stem cells (MSCs), are one of the most promising tool to manage DN progression, not only because they can be safely transplanted in human patients but also due to their proved renoprotective potential. The later, has been attributed to the capacity of MSCs to: i) reduce oxidative stress, ii) modulate chronic inflammation and macrophage infiltration, iii) avoid/revert fibrosis, iv) secrete trophic factors, and v) differentiate into pericytes, mesangial and tubular cells. The aim of this work was to evaluate whether the MSC renoprotective effect depends on DM etiology (T1DM vs T2DM). We used C57BL/6 mice rendered diabetic by the administration of a single high dose of streptozotocin, DN derived from T1DM (ND-T1DM) or C57BL/6 mice chronically exposed to high fat diet, DN derived from T2DM (DN-T2DM). DN-T1DM and DN-T2DM animals received intravenously a single dose of MSCs (0,5x106) at 8 and 25 weeks of diabetes respectively, since at this time diabetic mice were in an stage in which albuminuria was present, but most of the renal structures were still well preserved. Renal failure did not progress in MSC-treated mice, while in untreated mice albuminuria gradually increased in both animal models. These changes were correlated with morphological alterations including: mesangial expansion, podocyte loss, increased glomerulosclerosis index and tubular fibrosis. The observed renoprotective effects of MSC were not related to a reversion of the DM state. In order to study the homming of MSCs in the kidney, donor cells were isolated from mice that constitutively express GFP in all their tissues (MSCGFP). The presence of MSCGFP was assessed in 2 and 8 weeks after administration, by flow cytometry and immunohistofluorescence. We found donor cells in the kidney of diabetic mice (type 1 and type 2), but not in normal mice. Although donor cells were found in the kidney of treated mice, their scarcity suggests that the improvement in kidney function was not mediated by the differentiation of MSC into renal cells, so we suppose the participation of paracrine mechanisms to limit the progression of DN in MSC-treated mice.