There are no studies documented the role of RAS in

There are no studies documented the role of RAS in the differentiation of MSCs into IPCs but there are previous studies indicating that Ang II receptors exhibit opposing actions on MSCs differentiation, into other cell types rather than IPCs. The blockade of AT2R was reported to suppress MSCs differentiation into cardiomyocytes, whereas AT1R blockade induced the cardiomyocyte formation [18]. Otherwise, there is another study documented that the blockade of AT1R suppressed MSCs differentiation into adipocytes, whereas AT2R blockade promoted the adipocyte formation [16]. Moreover, it has been reported that in AT2R knockout mice, BM-derived MSCs did not improve the neurological variables and worsen survival. Pre-treatment with valsartan, AT1R blocker, improved the survival effect of BM-derived MSCs grafting [28]. Our findings agree with the results of [28] and [18]; exhibiting that the blockade of AT1R binding with Ang II in BM-derived MSCs lead to the direction of Ang II to bind with AT2R resulting in the differentiation of MSCs into IPCs. The explanation of why the activation of AT1R or AT2R induces MSCs differentiation toward one cell lineage rather than another is unknown yet. Perhaps it depends on the specificity of particular cell types or other unexamined factors [15]. We hypothesize that the local RAS possesses autocrine effects in MSCs, directing them to differentiate into IPCs. Our hypothesis can be supported by previous researches which hypothesized that local RAS exerts autocrine and paracrine functions on MSCs, directing them to differentiate into specialized ISO-1 such as cardiocytes, smooth muscle cells, and adipocytes [16], [17], [18].
Conclusion In conclusion, we observed a role of local RAS in regulating the differentiation of MSCs into IPCs through AT2R activation. This finding can possess potential implication for enhancing the differentiation of MSCs into IPCs. More studies are required to investigate the role of local RAS with other signaling pathways reported to regulate the differentiation of MSCs into IPCs in order to improve the outcome of MSCs as a source for IPCs. Additionally, more studies are needed to confirm the beneficial synergistic effects of different mechanisms regulating the MSCs differentiation into IPCs in different animal models in order to provide information which can support the scaling up for clinical implementation in patients suffering from T1DM or severe type 2 DM.
Competing interests
Acknowledgment We thank National Research Centre, Egypt for the financial assistance (14/2/2).
Introduction Angiotensin-converting-enzyme inhibitors (ACEI), which were introduced in clinical practice in 1980 and angiotensin II receptors antagonists; previously known as angiotensin II receptors blockers (ARBs), are two of the most commonly used drugs for the control of blood pressure over the last two decades [1]. These two groups have 4 positive attributes: they generate cardiovascular protection and lead to a decreased incidence of ischemic events and their complications; their early implementation is associated with increased survival rates after myocardial infraction and with a better heart function; on the other hand, they are effective in the treatment of both cardiac dysfunction and hypertension; and finally, they seem to delay the progression of diabetic nephropathy [2]. They act by blocking the shift from angiotensin I to angiotensin II (generating higher levels of bradykinin) in the case of ACEI and by increasing angiotensin levels (without increasing bradykinin) in the case of ARBs, and this last group is more selective with regard to the suppression of the effects of angiotensin II3. These mechanisms make it possible to achieve a good control of blood pressure. During anesthesia (either general or epidural), when the sympathetic tone is inhibited, the maintenance of arterial pressure will rely more predominantly on the renin-angiotensin axis or the vasopressin axis. If two of these systems are inhibited and one of these drugs is administered, the hypotension may adopt a more aggressive form of presentation [3]. This fact could account for the appearance of cases of refractory hypotension related to the administration of these drugs during anesthesia [4], [5], and it might justify the recommendation to withhold them prior to its induction.