Chronic kidney disease (CKD) affects 1 in 10 members of the general population, placing these patients at an increasingly high risk of kidney failure. Despite the significant burden of CKD on various healthcare systems, there are no effective cures that reverse or even halt its progression. In recent years, human bone-marrow-derived mesenchymal stromal cells (BM-MSCs) have been recognised as a novel therapy for CKDs, owing to their well-established immunomodulatory and tissue-reparative properties in preclinical settings, and their promising safety profile that has been demonstrated in patients with CKDs from several clinical trials. However, renal fibrosis (scarring), a hallmark of CKD, has been shown to impair the viability and functionality of BM-MSCs post-transplantation. This has suggested that BM-MSCs might require a pre-treatment or adjunct therapy that can enhance the viability and therapeutic efficacy of these stromal cells in chronic disease settings. To address this, recent studies that have combined BM-MSCs with the anti-fibrotic drug serelaxin (RLX), have demonstrated the enhanced therapeutic potential of this combination therapy in normotensive and hypertensive preclinical models of CKD. In this review, a critical appraisal of the preclinical data available on the anti-fibrotic and renoprotective actions of BM-MSCs or RLX alone and when combined, as a treatment option for normotensive vs. hypertensive CKD, is discussed.
Background and Purpose: This study investigated the reno-protective
effects of a highly selective AT2R agonist peptide, β-Pro7Ang III in a
mouse model of acute kidney injury (AKI). Experimental Approach:
C57BL/6J mice underwent either sham surgery or unilateral kidney
ischemia-reperfusion injury (IRI) for 40 minutes. IRI mice were treated
with either β-Pro7Ang III or perindopril and at 7 days post-surgery the
kidneys analysed for histopathology and the development of fibrosis and
matrix metalloproteinase (MMP)-2 and -9 activity. The association of the
therapeutic effects of β-Pro7Ang III with macrophage number and
phenotype was determined in vivo and in vitro. Key Results: Decreased
kidney tubular injury, interstitial matrix expansion and reduced
interstitial immune cell infiltration in IRI mice receiving β-Pro7Ang
III treatment was observed at day 7, compared to IRI mice without
treatment. This correlated to reduced collagen accumulation and MMP-2
activity in IRI mice following β-Pro7Ang III treatment. FACS analysis
showed a reduced number and proportion of CD45+CD11b+F4/80+ macrophages
in IRI kidneys in response to β-Pro7Ang III, correlating with a
significant increase in M2 macrophage markers and decreased M1 markers
at day 3 and 7 post-IR injury, respectively. In vitro analysis of
cultured THP-1 cells showed that β-Pro7Ang III attenuated
lipopolysaccharide (LPS)-induced tumour necrosis factor-α (TNF-α) and
interleukin (IL)-6 production but increased IL-10 secretion, compared to
LPS alone. Conclusion and Implications: Therapeutic delivery of
β-Pro7Ang III was renoprotective via alteration of macrophage phenotype
and anti-inflammatory cytokine release, therefore mitigating the
downstream progression of ischemic AKI.
Class A, rhodopsin‐like, G‐protein‐coupled receptors (GPCRs) are by far the largest class of GPCRs and are integral membrane proteins used by various cells to convert extracellular signals into intracellular responses. Initially, class A GPCRs were believed to function as monomers, but a growing body of evidence has emerged to suggest that these receptors can function as homodimers and heterodimers and can undergo functional crosstalk to influence the actions of agonists or antagonists acting at each receptor. This review will focus on the angiotensin type 1 (AT1) and type 2 (AT2) receptors, as well as the relaxin family peptide receptor 1 (RXFP1), each of which have their unique characteristics but have been demonstrated to undergo some level of interaction when appropriately co‐expressed, which influences the function of each receptor. In particular, this receptor functional crosstalk will be discussed in the context of fibrosis, the tissue scarring that results from a failed wound‐healing response to injury, and which is a hallmark of chronic disease and related organ dysfunction.
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