Microplastics (MPs) are defined as plastic fragments (fibers, particles or films) between 1 µm and 5 mm of size, while nanoplastics are below 1 µm. MPs can be categorized as primary or secondary. Primary MPs are small plastic pieces produced as such, while “secondary MPs” are plastic fragments deriving from the corruption and fragmentation of larger plastic pieces through physical, chemical or biological processes [1]. MPs occur in the environment through many routes: abrasion and erosion, wear and tear pf polymers, agricultural practices, industrial waste, fishing activities, garbage patches and the textile and clothing industry. Textile microfibers are one of the most important sources within primary microplastics. Laundering 6 kg of synthetic materials could release between 137–728 fibres per wash [2]. Microfibers can enter the environment throughout the supply chain of the fashion industry, from textile fabrication and clothing manufacturing to including domestic laundry activities [3]. Plastic production every year is increasing, and reached 368 million tons/year production worldwide in 2020 [4].

MPs have been detected in soil, fresh water, sea water and the atmosphere, and they have also been found in seafood, sea salt and various foods [5]. They have definitively entered into the human food cycle, becoming ubiquitous and representing an environmental threat [6]. A study performed by Cox et al. estimated an annual ingestion of 39,000–52,000 particles and a global exposition of 74,000–121,000 per year [7]. Moreover, the presence and detrimental effects of MPs in marine fauna have been demonstrated. Several studies performed on animals showed the ability of MPs to cross cell membranes and deposit on organs and tissues, causing oxidative stress, inflammation and metabolic disorders [8].

In consideration of this increasing evidence, MPs have become a growing medical concern in recent years and increasing studies have been published investigating the presence of MPs in human tissues and fluid. Surprisingly, almost the entirety of the studies showed the presence of MPs in organs and tissues analyzed such as the placenta, lungs, liver and blood, but their potential health-damaging consequences are still being debated. Moreover, an increasing amount of research on the toxicity of MPs on human cells and animal models has been carried out, and several studies into human cell lines have shown inhibition of cell growth and various molecular alterations [9]. Processes through MPs reaching organs and tissues are still a matter of research: nanoparticles can cross cellular membranes, while for bigger particles, mechanisms of endo and exocytosis are probably more involved. A pivotal role seems to be played by the formation of a coating of eco-coronas composed of biomolecules (e.g., proteins, lipids) that enhances the internalization of MPs into cells [10].

2. Microplastics Effects on Kidney Tissues and Cells

The growing concern among the medical community about the impact of MPs on human health has influenced the increasing number of studies performed in the last few years on human tissues and cells. Even though this trend refers to nephrology too, robust evidence on the effect of MPs and its compounds on kidney cells and tissues is still lacking. Most of the studies performed on nanoplastics (NPs) and MPs’ toxicity on kidney have been published in the last two years. Li et al. showed that PS-NPs worsen lipopolysaccharide-induced apoptosis in mouse kidney cells through the oxidative stress–endoplasmic reticulum pathway ^[11][38]. Furthermore, Tang et al. demonstrate nephrotoxicity in mice related to inflammation, oxidative stress and lipid disturbance ^[12][39]. After 6 weeks’ exposure to PS-NPs, the murine kidney index resulted in being decreased and presented tubular atrophy, glomerular collapse and inflammatory cells’ infiltration leading to decreased kidney function. Although some studies investigated NPs and MPs together, they have very peculiar characteristics due to their different size. Stability in biological solutions, formation of protein corona, absorption and intake by cell and tissues are markedly different among nano- and microparticles, making difficult comparisons between their effects in vivo and in vitro. The evidence supporting a potential toxic effect of MPs on kidneys (Table 1). A first pioneering study performed by Deng et al. in 2017 investigated the tissue accumulation and toxicity of PS-MPs using fluorescent microspheres of 5 and 20 µm in mice ^[13][40]. They demonstrated kidney deposition of MPs in mice. Moreover, the results showed oxidative stress, energy and lipidic metabolism alteration through metabolomic analysis. PS-MPs effects were further examined in another study in kidney tubular cells (HK2) and mice. Researchers confirmed the accumulation of MPs in kidneys in mice and uptake by HK2 ^[14][41]. Results suggested PS-MPs induce an increase in mitochondrial ROS, ER stress-related proteins, inflammation and autophagy biomarkers. Meng et al. corroborated the detrimental effects of PS-MPs in kidneys of mice through oxidative stress and inflammation. Significant increases in SOD, GSH-Px and significant inhibition of CAT in mice exposed to PS-NPs and PS-MPs were observed ^[15][42]. TNF-α, IL-6, IL-10 and MCP-1 resulted in being significantly increased too. Overall, PS-MPs seemed to cause increased mortality, weight loss and histologically proven kidney damage in mice. Meng et al. confirmed inflammation induced by PS-MPs through the activation of NF-κB in another study performed on chicken ^[16][43]. They showed that PS-MPs induce the alteration of necroptosis via RIP1/RP3/MLKL signaling too. The activation of ROS by PS-MPs was also demonstrated by Goodman et al. in vitro on human embryonic kidney cells (HEK293) ^[17][44]. They used 1 µm PS-MPs at relevant environmental concentrations for a 24–72 h time frame. They showed significant morphological changes in HEK293 increased ROS expression and lowered gene expression of antioxidant markers (SOD2, CAT, GAPDH) indicating lowering glycolytic activity, thus the altered ability of HEK293 to contrast ROS. Altogether, these alterations affect the overall function of kidney cells. The cytotoxicity of PS-MPs has been detected on HEK293 within 24 h of exposure ^[18][45]. Oxidative stress and inflammation in kidney cells by PS-MPs could also be due to the inhibition of HO activity and induction of cytokines (IL-1β, IL-2, IL-6, TNF-α, TIMP-1 and 2) at low-noncytotoxic MPs concentration. At higher MPs’ concentrations (300 ng/mL), Chen et al. showed that PS-MPs induce autophagy and can diminish inflammation via NLRP-3 inhibition ^[12][39]. Furthermore, autophagy and apoptosis have been shown to be induced by PS-MPs by activating the AMPK/ULK1 pathway via ROS ^[19][46]. Indeed, ROS/AMPK/ULK1 and Ppargc1α/Mfn2 pathways resulted in being significantly increased after conditioning with PS-MPs and Di(2-ethylhexyl)phthalate (DEPH), an environmental plastic compound frequently used to strength plastic products. In real life, MPs are frequently combined with other pollutants present in the environment or are used as plasticizers and associated with polymers in plastic industrial production. As demonstrated by Sun et al., DEPH and PS-MPs have a synergistic toxic effect on kidney cells ^[19][46]. This mechanism, also known as the “trojan horse effect”, has also been investigated for organic and metallic contaminants ^[20][47]. In a mouse kidney injury model, toxicological effects of MPs combined with cadmium revealed kidney damage through oxidative stress, autophagy, apoptosis and fibrosis. In particular, 5 µm of MPs has been shown to adsorb cadmium and accumulate in the kidneys of mice inducing a severe biological response ^[20][47]: a decrease in antioxidant enzyme activities (SOD and CAT), increased autophagy markers LC3-II and autophagy early markers ATG5 and 7 and Beclin-1 and finally an increase in kidney fibrosis markers such as α-SMA, TGF-β1 and COL4A, ultimately leading to an alteration of kidney tissue structure and nephrotoxicity. Interestingly, the chronic exposure to MPs has been investigated in a well-written study performed on mice ^[21][48]. Mice were treated with different diameters of MPs (80 nm, 0.5 μm, 5 μm). Histology analysis demonstrated that an 8-week exposition to PS-MPs induced mesangial matrix expansion, endocapillary proliferation, tubulointerstitial fibrosis and inflammatory infiltration in mice. Moreover, molecular analysis revealed oxidative stress induction through increased malonaldehyde levels and increased levels of inflammation markers IL-1β and MCP-1. Fibrosis was demonstrated histologically with Masson staining showing high-collagen deposition and by molecular investigations showing higher α-SMA expression after exposure to MPs. Moreover, serum creatinine levels resulted in the 5 μm MPs’ group compared to the control group. To explore the mechanisms behind the development of renal fibrosis in MPs’ exposure a transcriptome analysis was performed. With the contribution of Gene Ontology Analysis, chronic exposure resulted in being enriched in immune-related signals and is strongly associated with circadian rhythm ^[21][48].