Emerging Paradigms in Chronic Kidney Ischemia

Eirin, Alfonso; Textor, Stephen C.; Lerman, Lilach O.

doi:10.1161/hypertensionaha.118.11082

Cited by 19 publications

(18 citation statements)

References 68 publications

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“…In the current study, we used a swine model that recapitulates human RAS to test the hypothesis that chronic renal ischemia and hypertension alter the gene expression profile of STCs. RAS is characterized by repeated episodes of insults mimicking AKI [13,14], and therefore represents a relevant model to study this endogenous repair mechanism. While ischemia-reperfusion injury activates STCs capable of repairing the damaged kidney, the effects of chronicity renal ischemia and hypertension on these cells remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Renal Artery Stenosis Alters Gene Expression in Swine Scattered Tubular-Like Cells

Nargesi

Zhu

Liu

et al. 2019

IJMS

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Background: Scattered tubular-like cells (STCs) proliferate and differentiate to support neighboring injured renal tubular cells during recovery from insults. Renal artery stenosis (RAS) induces renal ischemia and hypertension and leads to loss of kidney function, but whether RAS alters renal endogenous repair mechanisms, such as STCs, remains unknown. We hypothesize that RAS in swine modifies the messenger RNA (mRNA) profile of STCs, blunting their in vitro reparative capacity. Methods: CD24+/CD133+ STCs were isolated from pig kidneys after 10-weeks of RAS or sham (n = 3 each) and their gene cargo analyzed using high-throughput mRNAseq. Expression profiles for upregulated and downregulated mRNAs in RAS-STCs were functionally interpreted by gene ontology analysis. STC activation was assessed by counting the total number of STCs in pig kidney sections using flow cytometry, whereas cell proliferation was assessed in vitro. Results: Of all expressed genes, 1430 genes were upregulated and 315 downregulated in RAS- versus Normal-STCs. Expression of selected candidate genes followed the same fold change directions as the mRNAseq findings. Genes upregulated in RAS-STCs were involved in cell adhesion, extracellular matrix remodeling, and kidney development, whereas those downregulated in RAS-STCs are related to cell cycle and cytoskeleton. The percentage of STCs from dissociated kidney cells was higher in RAS versus Normal pigs, but their proliferation rate was blunted. Conclusions: Renal ischemia and hypertension in swine induce changes in the mRNA profile of STCs, associated with increased STC activation and impaired proliferation. These observations suggest that RAS may alter the reparative capacity of STCs.

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Section: Discussionmentioning

confidence: 99%

Renal Artery Stenosis Alters Gene Expression in Swine Scattered Tubular-Like Cells

Nargesi

Zhu

Liu

et al. 2019

IJMS

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“…(16) In the setting of significant RVD, further reduction of renal blood flow and hypoxia trigger inflammation, oxidative stress and pro-fibrotic pathways, leading to scarring and further deterioration of renal function (ischemic nephropathy). (17) Importantly, recent clinical trials and experimental studies indicate that restoration of large vessel patency alone is not enough to regain kidney function in most patients with atherosclerotic RVD. (18,19) The limited number of currently-available strategies for effectively modulating RVD and the realization that the natural history of this disease involves transition from a hemodynamic component to a pro-inflammatory and pro-fibrotic disease highlight the need for a paradigm shift in therapy.…”

Section: Renovascular Diseasementioning

confidence: 99%

Progress toward the Clinical Application of Mesenchymal Stromal Cells and Other Disease-Modulating Regenerative Therapies: Examples from the Field of Nephrology

et al. 2021

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Drawing from basic knowledge of stem cell biology, embryonic development, wound healing and aging, regenerative medicine seeks to develop therapeutic strategies that complement or replace conventional treatments by actively repairing diseased tissue or generating new organs and tissues. Among the various clinical translational strategies within the field of regenerative medicine, several can be broadly described as promoting disease resolution indirectly through local or systemic interactions with a patient's cells without permanently integrating or directly forming new primary tissue. In this review, we focus on such therapies, which we term disease modulating regenerative therapies (DMRT), and on the extent to which they have been translated into the clinical arena in four distinct areas of nephrology: renovascular disease (RVD), sepsis-associate acute kidney injury (SA-AKI), diabetic kidney disease (DKD) and kidney transplantation (KTx). As we describe, the DMRT that has most consistently progressed to human clinical trials for these indications is mesenchymal stem/stromal cells (MSCs), which potently modulate ischemic, inflammatory, pro-fibrotic and immune-mediated tissue injury through diverse paracrine mechanisms. In KTx, several early-phase clinical trials have also tested the potential for ex vivo-expanded regulatory immune cell therapies to promote donor-specific tolerance and prevent or resolve allograft injury. Other promising DMRT, including adult stem/progenitor cells, stem cell-derived extracellular vesicles and implantable hydrogels/biomaterials remain at varying pre-clinical stages of translation for these renal conditions. To date (2021), no DMRT has gained market approval for use in patients with RVD, SA-AKI, DKD or KTx and clinical trials demonstrating definitive, cost-effective patient benefits are needed. Nonetheless, exciting progress in understanding the disease-specific mechanisms of action of MSCs and other DMRT, coupled with increasing knowledge of the pathophysiological basis for renal tissue injury and the experience gained from pioneering early-phase clinical trials provide optimism that impactful, regenerative treatments for diverse kidney diseases will emerge in the years ahead.

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“…On the other hand, the restoration of renal blood flow (RBF) by percutaneous transluminal renal angioplasty (PTRA) is not associated with resolution of symptoms. Emerging experimental findings provide novel insights on the role of micro-inflammation, oxidative stress and microvascular remodelling [22] in the pathogenesis of hypertension and in CKD patients affected by RAS-IN. RAS may be unilateral; in these cases, CKD may be the consequence of exposure to persistently high BP levels, configuring HTN.…”

Section: Ischemic Nephropathy Related To Renal Artery Stenosis (In-ras)mentioning

confidence: 99%

“…MCP-1 and PAI-1) mediators on glomerular and tubule-interstitial structures induced by ischemia [24]. As proof of a pathogenetic role of inflammatory mediators, recent experimental studies showed that the reduction of renal inflammation is associated with renal function improvement [22].…”

Section: Atherosclerotic Renovascular Disease (Arvd)mentioning

confidence: 99%

Atherosclerotic-nephropathy: an updated narrative review

et al. 2020

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The increased prevalence of chronic kidney disease (CKD) in elderly patients recognizes, as main cause, the long-term exposure to atherosclerosis and hypertension. Chronic ischemic damage due to critical renal arterial stenosis induces oxidative stress and intra-renal inflammation, resulting in fibrosis and microvascular remodelling, that is the histological picture of atherosclerotic renal vascular disease (ARVD). The concomitant presence of a long history of hypertension may generate intimal thickening and luminal narrowing of renal arteries and arterioles, glomerulosclerosis, interstitial fibrosis and tubular atrophy, more typically expression of hypertensive nephropathy. These complex mechanisms contribute to the development of CKD and the progression to End Stage Kidney Disease. In elderly CKD patients, the distinction among these nephropathies may be problematic; therefore, ischemic and hypertensive nephropathies can be joined in a unique clinical syndrome defined as atherosclerotic nephropathy. The availability of novel diagnostic procedures, such as intra-vascular ultrasound and BOLD-MRI, in addition to traditional imaging, have opened new scenarios, because these tools allow to identify ischemic lesions responsive to renal revascularization. Indeed, although trials have deflated the role of renal revascularization on the renal outcomes, it should be still used to avoid dialysis initiation and/or to reduce blood pressure in selected elderly patients at high risk. Nonetheless, lifestyle modifications (smoking cessation, increased physical activity), statins and antiplatelet use, as well as cautious use of renin-angiotensin system inhibitors, remain the main therapeutic approach aimed at slowing the renal damage progression. Mesenchymal stem cells and Micro-RNA are promising target of anti-fibrotic therapy, which might provide potential benefit in ARVD patients, though safety and efficacy profile in humans is unknown too.

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Emerging Paradigms in Chronic Kidney Ischemia

Cited by 19 publications

References 68 publications

Renal Artery Stenosis Alters Gene Expression in Swine Scattered Tubular-Like Cells

Renal Artery Stenosis Alters Gene Expression in Swine Scattered Tubular-Like Cells

Progress toward the Clinical Application of Mesenchymal Stromal Cells and Other Disease-Modulating Regenerative Therapies: Examples from the Field of Nephrology

Atherosclerotic-nephropathy: an updated narrative review

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