DKD is a common complication of diabetes and can lead to abnormal levels of blood pressure, lipids, and glucose, which can further damage the kidneys and increase the risk of cardiovascular disease. It is important for individuals with diabetes to closely monitor and manage their blood sugar levels and to work with their healthcare provider to manage any other risk factors [53,54,55,56,57]. A lifestyle change is crucial for the diagnosis, control, and therapy of DM and related consequences [58].

Controlling level of blood glucose

It is estimated that about 20% of people with DM developed DKD irrespective of well-controlled blood glucose levels [59]. Certain clinical studies have shown that intensive blood glucose control can delay the progression of diabetic kidney disease and protect renal function such as development of microalbuminuria and reduced eGFR in diabetic patients [60]. To gentle the progression of DKD, initial DM patients must toughen glycemic control to eliminate the quantity of HbA1c to 7.0% or less, according to regulations from the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) [61] and Kidney Disease Outcomes Quality Initiative (KDOQI) [60]. However, some studies have found that HbA1c levels below 6.0% or above 9.0% are associated with an increased risk of death [62, 63]. Therefore, current international guidelines recommend an individualized approach to treatment intensity based on the patient’s characteristics and risk factors. This means that while the target HbA1c of 7% is a general recommendation, the individualized approach to treatment intensity will be taken into consideration which means the target may vary for different patients [60].

The significance of blood glucose control cannot be overstated. It directly influences the effectiveness of various therapeutic approaches, including stem cell therapies such as MSC-based treatments for diabetes. An illustrative example of this is highlighted in the meta-analysis conducted in 2016 [64]. Their study underscores the critical role of glucose control and its direct impact on the outcomes of stem cell therapy for diabetes. Notably, the study raises a pivotal consideration: the potential challenges associated with MSC-based treatment in the presence of diabetic ketoacidosis (DKA) if not managed correctly. The data from their meta-analysis suggests that individuals with DKA at the time of diagnosis may present unique challenges for stem cell therapy. One possible explanation for this suboptimal clinical response among DKA patients is the presence of very low β-cell reserve. Therefore, the success of MSC-based treatments for diabetes is intricately linked to meticulous glucose control and the avoidance of complications associated with DKA. These findings reiterate the importance of precise glucose management and patient selection within the context of stem cell therapy for diabetes, reinforcing the significance of individualized care.

Controlling body weight

Excessive body weight leads to insulin resistance, systemic inflammation, and metabolic dysregulation which in turn establish the detrimental effects on renal function. Thus, successful weight management, attained through lifestyle adjustments, dietary regulation, and routine physical exercise, serves as a crucial means not only to enhance glycemic control but also to diminish the risks and progression of DKD. As we delve into the multifaceted approach of DKD management, it is important to consider the innovative approaches such as the therapeutic potential of mesenchymal stem cells (MSCs) in the context of obesity, diabetes, and its related complications. In numerous investigations, the administration of human MSCs or MSC-derived conditioned media to diet-induced obese (DIO) mice resulted in a notable reduction in both body weight and fat mass. What is more, MSC therapy demonstrated a significant improvement in the metabolic parameters of obese mice, including enhanced insulin sensitivity and reduced levels of blood glucose and triglycerides [65]. Consequently, multiple MSC administrations shielded obese mice from the onset of metabolic syndromes linked to obesity, including diabetes, fatty liver disease, and cardiovascular impairment [66]. In another study, intravenous administration of human adipose-derived MSCs was employed in high-fat-diet-induced obese mice. This intervention led to reduced adipose tissue weight, adipocyte size, and fat mass, along with improved metabolic profiles. Additionally, it increased energy expenditure, upregulated metabolic genes, and induced a shift towards anti-inflammatory M2 macrophages in adipose tissue [67].

Blood pressure control

Strict blood pressure supervision in DKD patients can substantially lower albuminuria, delay loss of kidney function, and minimize the risks of heart disease [68]. The American Diabetes Association (ADA) recommends that people with diabetes aim to keep their blood pressure under 140/90 mmHg (1 mmHg = 0.133 kPa). For patients with cardiovascular disease or kidney failure, a lower blood pressure target of 130/80 mmHg is recommended. All other patients control their blood pressure at a target of 130/80 mmHg [69]. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial was a large randomized controlled trial that recruited participants with type 2 diabetes and randomized them to an intensive blood pressure therapy group or a standard blood pressure therapy group. The intensive therapy group aimed to achieve a systolic blood pressure of less than 120 mmHg, while the standard therapy group aimed to achieve a systolic blood pressure of less than 140 mmHg. The trial found that intensive blood pressure therapy reduced the incidence of cardiovascular events and overall mortality in the intensive therapy group compared to the standard therapy group. These findings support the use of more aggressive blood pressure targets in patients with type 2 diabetes to reduce the risk of cardiovascular disease [70,71,72].

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are commonly used as first-choice remedies for the treatment of DKD due to their ability to slow the progression of kidney damage and reduce the risk of cardiovascular disease. These drugs work by blocking the action of the angiotensin II hormone, which plays a key role in the development of kidney damage and hypertension. However, it is important to note that the combination of an ACEI with an ARB is generally contraindicated as it has been shown to increase the risk of kidney injury and hyperkalemia [73,74,75]. It has been reported that dual blockade of RAAS by using a combination of an ACEI and an ARB can lead to significant drops in blood pressure and severe renal failure in animal models, such as in spontaneously hypertensive rats receiving a low-sodium diet. The RAAS is a complex hormonal system that plays a key role in regulating blood pressure, electrolyte balance, and fluid volume in the body. Blocking the RAAS with drugs like ACEIs and ARBs can lead to decreased blood pressure and improved kidney function, but when both pathways are blocked, it can lead to a decrease of blood pressure to dangerous levels and severe renal failure [76].

According to the review outcomes of the ALTITUDE (Aliskiren Trial in Type 2 Diabetes That using Cardio-Renal Endpoints NCT00549757), these appointed subjects randomly in a controlled trial and evaluated the use of aliskiren as adjunctive therapy to an ACEI or ARB in individuals with T2DM, CKD, or CVDs. This trial elucidated that aliskiren as an alternative treatment regimen did not further enhance renal performances; instead, it slowed the succession of albuminuria [77, 78]. Unfortunately, the trial was terminated early due to an increased risk of adverse events in the aliskiren group compared to the placebo group. Compared to existing treatments, ACEI and ARB combined extended the major unfavorable responses, i.e., extreme kidney injury and hyperkalemia, in a comparable study called VA-Nephron-D (Veterans Affairs Nephropathy in Diabetes, NCT00555217). From the start of the therapy to the 2-year follow-up, the danger of serious kidney harm was likewise immeasurably greater [74, 79]. When taking medication for ACEI/ARB, the urine albumin to creatinine ratio (UACR), creatinine clearance (CCr), potassium levels in the blood, and serum amount must all be surveilled.

Control of blood lipids

DKD patients are highly compromised with vascular problems, which may lead to hyperlipidemia. It can disrupt the barrier function of endothelial cells while also endangering blood supply [80, 81]. The KDOQI guidelines advise statin-based treatment for lowering low-density lipoprotein cholesterol (LDL-C) levels to lessen the risk of atherosclerotic complications in DKD patients. According to a meta-analysis of cholesterol treatment, the incidence of significant cardiovascular events decreased by 23% for each mmol/L drop in LDL-C [82]. The “2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases development in collaboration with the EASD” recommend that in patients with arteriosclerotic cardiovascular diseases and diabetes or stage 3–4 CKD, LDL-C should be controlled to a target of less than 1.4 mmol/L (or 55 mg/dL) to reduce the risk of cardiovascular disease. This is a stricter target compared to the general population where the target is less than 2.5 mmol/L [83].

Low-protein diet

The reductions in proteinuria (the amount of protein in the urine) have been shown to be a comprehensive index of decreased renal and cardiovascular event risk in T2DM patients [84]. Regardless, a low-protein eating plan for DKD has ignited some talk. The American Diabetes Association (ADA) recommends that people with DKD should aim to control their protein intake by consuming about 0.8 g/kg of body weight per day (0.8 g kg−1 d−1). This is in contrast to higher levels of protein intake, which have been found to accelerate the decline of kidney function as measured by the glomerular filtration rate. This is because higher levels of protein intake can cause an increase in metabolic waste products that the kidneys must filter, which can lead to further damage [85]. Ingesting less protein, then again, would gainfully affect glucose, GFR power, or cardiovascular issues [86].

Use of new hypoglycemic drugs

RAAS (ACE inhibitors and ARBs) and metformin (anti-diabetic medication to control the glucose levels) can help to reduce the workload on the kidneys. These medications may be used together or as monotherapy to help slow the progression of DKD and protect kidney function [87, 88]. The development of DKD is undeniable and may require an urgent need for a novel treatment approach [89]. The pathological and molecular mechanisms of DKD are under study to develop more target based-drugs [90,91,92,93]. Three novel hypoglycemic remedies, including dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 inhibitors (SGLT2i) receptor agonists, and glucagon-like peptide 1 receptor agonists (GLP1-RA), show comprehensive renal protective effects [94]. Clinical trials have shown promising results, particularly for hypoglycemic drugs/inhibitors, such as SGLT2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors. In an animal or human clinical assessment, solutions like protein kinase C inhibitors, AGE inhibitors, endothelin receptors, Rho kinase, and TGF-β have shown promising positive effects and bring hope for the treatment of DKD. Other novel medicines that are still being researched include CCX140b [94], PF-00489791 [95], and NOX-E36 [96]. Moreover, current preclinical studies are investigating the patterns of multiple novel targets, including adiponectin and its receptors [97], NADPH oxidase [98], histone deacetylase [99, 100], and microRNA [101, 102] in DKD.

Currently, most drugs are being tested at different degrees of advancement. To predict DKD patients, there is a dire need to conduct extensive studies that utilize larger cohorts and randomly controlled trials. The pathophysiology of DKD is not yet fully comprehended, and there are only a few treatments that target signaling molecules or pathways. Moreover, while certain drugs have demonstrated efficacy in preclinical studies, they either do not advance to clinical trials or lack sufficient clinical trials to establish their effectiveness. Despite some drugs showing promising results for DKD, their safety profiles remain insufficient. As a result, we have a long way to go in treating DKD given these challenges. Traditional methods for treating DKD, like conventionally prescribed medicines, physiotherapy, and dietary treatment, are not always fruitful. To lessen the significant patient count and medical services load, innovative therapy models like cellular therapy are required. These techniques may hamper the development of DKD and contribute to repairing the defected organs without causing any severe side effects [74]. Mesenchymal stem cells (MSCs), i.e., adult stem cell treatment, are possibly the most favorable cellular therapy in the field of regenerative medicine. As they may be used systemically or locally to treat many diseases, due to their self-renewal and differentiation potential.

Mesenchymal stem cell therapy

The capacity to self-renew and give rise to cells from different lineages are two good qualities of stem cells. Interaction of MSCs with numerous human illnesses like diabetes mellitus, malignant growth (cancer), and neurodegenerative diseases like Parkinson’s and Alzheimer’s has been widely investigated. Stem cells can be classified based on their origin; embryonic stem cells, adult stem cells, and induced pluripotent stem cells. Adult stem cells are undifferentiated cells found in various tissues in the body that have the capacity to differentiate into multiple cell types of that specific tissue or organ. These stem cells incorporate MSCs, HSCs (hematopoietic stem cells), satellite cells, and MuSCs (muscle stem cells). Traditionally, MSCs were first isolated from bone marrow (BM-MSCs) and spleen from guinea pigs [103].

MSCs may generally be observed in the bone marrow, birth canal, umbilical cord blood, visceral fat, brain tissues, and several other tissues. Research has highlighted that MSCs are highly variable, exhibiting significant heterogeneity among various sources and even within the same source, which underscores the need for thorough characterization and quality control measures. Considering this, the International Society for Cellular Therapy (ISCT) made specific standards for all MSCs separated by various sources. In 2019, the ISCT introduced updated guidelines that aim to address the inherent heterogeneity of mesenchymal stem cells (MSCs). These guidelines encompass a variety of analytical methods designed to illustrate various functional properties of MSCs. These properties include the secretion of trophic factors, the modulation of immune cells, and their role in angiogenesis. The ISCT MSC committee has put forth recommendations for research studies in this field. These recommendations emphasize the importance of providing comprehensive information in the following key areas (i) tissue source origin (to highlight the tissue-specific properties associated with these cells), (ii) stemness properties (described by both in vitro and in vivo data), (iii) functional assays (employ a robust set of functional assays to assess the properties of MSCs in relation to their intended therapeutic mechanisms). Furthermore, evaluating MSC-based products involves a set of fundamental assays, which encompass donor screening; viability assessments; purity tests (including assessments for residual contaminants and pyrogenic/endotoxin presence); safety evaluations (such as bacterial, fungal, mycoplasma, viral tests, and tumorigenicity assays); identity assessments (including immunophenotypic profiles); and potency tests (comprising evaluations of multilineage differentiation, secretion profiles, CFU-f assays, and immunosuppressive properties). Incorporating these ISCT recommendations is crucial to ensuring that research in this field adheres to established standards and guidelines for the characterization and assessment of MSCs. These guidelines serve as a foundational reference point for evaluating the quality and therapeutic potential of MSC-based interventions across various clinical applications [104]. As per the ISCT’s MSC criteria, genuine human MSCs should not display specific surface markers, which include HLA-DR (MHC class II), CD19, CD14, CD34, CD45, and the B-cell antigen receptor’s alpha chain, CD79a. Conversely, MSCs are expected to exhibit the presence of positive surface markers such as Thy-1 (CD90), 5′-nucleotidase (CD73), and endoglin (CD105). In an in vitro setting, MSCs should also showcase their ability to undergo differentiation into adipogenic, osteogenic, and chondrogenic lineages while manifesting the corresponding phenotypic characteristics [105]. Notwithstanding these attributes, MSCs additionally produce bioactive substances with immunoregulatory properties that advance tissue redesigning and fixing.

MSCs origin and expansion

The most common isolation sources of MSCs include adipose tissue, bone marrow, and umbilical cord. Certain in vitro and in vivo studies subjected their investigation routes on the regenerative potential of MSCs derived from aged and young donors. The majority of the investigations looked at how donor age correlated with MSC performance, which can range from 16 months to 90 years old. The studies showed that samples taken from older individuals exhibit lower MSC frequency, colony forming unit (CFU) efficiency, population doubling rate, osteogenic, and differentiation potential with increased risks of senescence. Senescence in MSCs can greatly impact their regenerative potential, reducing the ability to differentiate into specific cell types, to recruit macrophages, and to polarize them towards the anti-inflammatory M2 phenotype. This highlights the importance of obtaining MSCs from young and healthy donors when cultivating them for therapeutic purposes, and to avoid the expansion of senescent cells [106].

Umbilical cord MSCs

In the recent decade, MSCs derived from umbilical cord (UC) blood, placenta, and amnion have presented numerous advantages over MSCs acquired from bone marrow and adipose tissues (AT). A higher proliferation rate, increased proliferation capacity, and longer lifespan in comparison to BM and AT-MSCs was observed. Previously conducted studies have also observed the expansion capacities of UC-MSCs as they can be proliferated over several passages (up to 16) with the retention of normal karyotype and avoiding the senescence [107, 108]. Conversely, there are some shortcomings to successfully isolating and expanding UCB-MSCs; most notably the low frequency of MSC clones compared to UC, which has a rich supply of highly proliferative MSCs that are characterized by: compared to BM-MSCs, it has a uniform phenotype of adherent, spindle-shaped fibroblast-like cells in primary culture, a higher isolation yield (5 × 104–5 × 105 cells from 1 cm3 of UC tissue), a higher frequency of colony forming units (CFU)-F, and a shorter DT (24 h) [109].

Furthermore, the UC-MSCs secretome maybe comparable to the BM-MSCs secretome in its abundance of angiogenic factors. However, a previously conducted study points out that the isolation of MSCs, cell freezing conditions, and exposure of cells in cryoprotectants still needs further research [110]. Future research stating the pros and cons of using fetal tissue-derived MSCs requires large-scale investigations. Similarly, another study presented their findings regarding MSCs derived from young donors. They observed a faster proliferation rate, shorter doubling time, and efficiency in secreting cytokines for tissue regeneration in comparison to MSCs obtained from older or adult donors. The MSCs obtained from aged individuals presented increased chromosomal instability, employing genetic changes or mutations. Also, they were more susceptible to oxidative stress, which can lead to damage to DNA, proteins, and other cellular components and can negatively impact the cells’ ability to function properly. The idea that aging affects cell proliferation holds great importance. Cell division and proliferation capacity slows down as we age due to morphological and cellular changes. The presence of aging-related markers like SA-β-gal, P16, and p21 may also be the cause of the observed differences in proliferation between MSCs of varying ages [111]. It is important to remember that MSCs are a type of adult stem cell that can grow into many different kinds of cells, but where they origin from, affects the therapeutic purpose.

iPSC-MSCs

The indefinite in vitro culture capability of induced pluripotent stem cells (iPSCs) and their potential to differentiate into various cell types, including MSCs, make them a promising alternative to BM-MSCs for cell and gene therapy applications. The study [112] showed that iPSC-MSCs can be generated in clonal expansion and differentiated into various cell types including osteoblasts, adipocytes, and chondrocytes, and promote tissue regeneration. This enhanced regenerative potential and decreased senescence of iPSC-MSCs has been suggested to be due to higher telomerase activity compared to BM-MSCs, which may contribute to a decrease in the possibility of losing potency in the long-term culture of MSCs. Additionally, the iPSC-MSCs have the advantage of being derived from autologous cells which makes them more suitable for therapies in personalized medicine. Also, future clinical trials would better unveil the actual results of this domain [113].

Molecular mechanisms of MSC-based therapy for DKD

Experimental studies have shown promising results in using MSCs for relieving DKD, as outlined in Table 1, although the exact molecular mechanisms are still being investigated. MSCs are multipotent cells that can differentiate into various cell types, including glomerular endothelial cells, when stimulated appropriately. The process of homing MSCs to damaged kidneys involves several molecules, including chemokine receptors, adhesion proteins, and the matrix metalloproteinases (MMPs) family, with stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 playing a significant role in MSC migration to the site of kidney damage [114]. In vitro studies have found that MSCs display a unique cellular behavior known as nonapoptotic membrane blebbing, which is similar to that of metastatic tumor cells. This behavior allows MSCs to migrate through the endothelium and overcome the basal barrier through the action of MMPs, particularly MMP2 and MT1-MMP. This allows MSCs to move through the tissue barriers and reach the damaged site [115]. However, despite the potential of MSCs to migrate to injured tissue and differentiate into functional replacement tissue, most studies have shown that only a small fraction of systemically administered cells can actually achieve this. Moreover, only a small percentage of transplanted cells can successfully differentiate into functional tissue. Additionally, the administered cells are almost undetectable in other organs within 24 h, suggesting that their therapeutic effects may be mainly due to their paracrine activity rather than their differentiation potential [116]. Therefore, more research is needed to fully understand the molecular mechanisms underlying MSC-based therapy for DN and to improve the efficacy of this approach.

Table 1 MSCs administration for DKD in preclinical studies

According to [117], many preclinical experimental models of DM and diabetic nephropathy have shown that exogenously administered MSCs can modulate a variety of pathophysiologic processes that contribute to the progressive renal injury and functional loss seen in DKD through paracrine-mediated actions and cell-cell interactions. The evidence suggests that intravenous or other routes of MSC administration can have beneficial effects on the kidneys in diabetes models, both directly through the transfer of MSCs and their mediators to distinct renal compartments and indirectly through the reduction of glycemia and systemic inflammation [117]. Several mediators have been identified that play a crucial role in the direct and indirect paracrine effects of MSCs in DKD. One of these mediators is indoleamine 2,3-dioxygenase (IDO), which is a potent immunomodulatory enzyme that can inhibit T-cell activation and proliferation. IDO can be induced in MSCs in response to inflammatory stimuli, and its expression can lead to the production of immunosuppressive metabolites such as kynurenine and tryptophan, which can further inhibit immune cell function. Another mediator associated with the paracrine effects of MSCs in DKD is prostaglandin E2 (PGE2). PGE2 is a lipid mediator that has been shown to play a key role in the regulation of T cell differentiation, particularly in the promotion of regulatory T cell (Treg) differentiation. In addition to IDO and PGE2, interleukin-10 (IL-10) has also been identified as an important mediator of the paracrine effects of MSCs in DKD. IL-10 is an anti-inflammatory cytokine that is produced by macrophages in response to phagocytosis of apoptotic MSCs. IL-10 can promote tissue repair and regeneration by suppressing inflammation and promoting the differentiation of pro-repair immune cells [118]. The outcomes received from DKD and DM models elucidated that MSCs can exert their potential when used as MSCs-derived conditioned medium (cocktail of cytokines, growth factors) or exosomes. The use of MSC-derived conditioned medium and exosomes offers advantages over MSCs, as it eliminates the need for isolation and expansion, reduces the risk of immune rejection, and allows for tailored administration of bioactive molecules [119].

MSCs have been found to have positive effects on the kidneys, leading to reductions in various negative processes such as glomerular size, podocyte apoptosis, glomerular matrix expansion/sclerosis, peritubular interstitial fibrosis, renal tubular epithelial cell death and dedifferentiation, tubulointerstitial fibrosis, and microvascular rarefaction. As a result, these effects are linked to decreased albuminuria (an indication of kidney damage) and stabilization of glomerular filtration rate (GFR), which is a key measure of kidney function [120].

MSCs-derived exosomes and their role in DKD

MSCs can secret a large number of RNAs, lipids, and a variety of soluble factors packaged in extracellular vesicles (exosomes), as well as act through their paracrine function, The promising biological capacities of exosomes including biocompatibility, stability, low toxicity, and effectual transport of molecular cargos, make them a suitable candidate in cellular therapy. Studies have shown that MSCs-Exos may have beneficial effects in the treatment of neurological, respiratory, cartilage, renal, cardiac, liver diseases, bone regeneration, and cancer [143]. Compared to MSCs alone, MSCs-exosomes have demonstrated superior therapeutic and regenerative effects. Nearly, all DKD renal resident cells exhibit an autophagy disorder when diabetic [144]. Exosomes made from human urine stem cells, adipose tissue-derived MSCs, BM-MSCs, human umbilical cord MSCs, endometrial fluid, and amniotic fluid are helpful in the treatment of DKD [145]. The BM-MSCs-exosomes have potential therapeutic benefits in the treatment of DKD. Studies in animal models of DKD have shown that BM-MSC-Exos can upregulate autophagy, which is an important cellular process that helps to remove damaged proteins and organelles. This upregulation of autophagy is thought to be mediated by the inhibition of the mTOR signaling pathway, which is known to be dysregulated in DKD. The inhibition of this pathway leads to improved renal function, as evidenced by decreased levels of SCr, blood urea nitrogen (BUN), and urine albumin (UALB) in DKD mice after multiple injections of BM-MSC-Exos. The BM-MSC-Exos also have an anti-fibrotic action, they can reduce renal fibrosis, which is a key contributor to the progression of DKD. Additionally, the injections were able to reduce mesangial dilatation, a characteristic feature of diabetic kidney disease [146].

Recent research has shown that exosomes acquired from human urine stem cells can transport miR-16-5p, which is a small non-coding RNA molecule. This miRNA has displayed an important role in preventing podocyte apoptosis and inhibiting the expression of VEGF-A (vascular endothelial growth factor A), which is a key mediator of diabetic nephropathy. This inhibition of podocyte apoptosis shows potential in alleviating podocyte damage and slowing the progression of DKD. Through its intricate interactions at the molecular level, miR-16-5p emerges as a prospective facilitator for the restoration of podocyte quantities and the reinforcement of renal resilience. Through the downregulation of VEGF-A expression, a crucial contributor to the pathogenesis of diabetic nephropathy, miR-16-5p actively contributes to the modulation of podocyte behavior and the alleviation of disease-related processes. This study provides a fresh perspective for which future investigations for DN may be established upon. However, being a pre-clinical study, further investigations into the finer mechanistic details are required in future studies. In addition to this, exosomes from human urine stem cells have been found to reduce inflammation, ameliorate podocyte injury, and improve renal function in a mouse model of DKD [147]. Understanding how these molecules interact with target cells and how they influence the development of DKD could open new perspectives in the field of regenerative medicine. Studies have shown that miR-146a-5p can target the TRAF6-STAT1 signaling pathway, which is a key mediator of inflammation in the kidney. By targeting this pathway, miR-146a-5p is able to promote the polarization of M2 macrophages, which are a type of immune cell that have anti-inflammatory properties. This promotes a shift from the pro-inflammatory M1 macrophage phenotype to the anti-inflammatory M2 phenotype. Additionally, this shift in macrophage polarization leads to a suppression of renal inflammation and the restoration of renal function in preclinical models of kidney disease, such as diabetic nephropathy [