The Role of Pyroptosis in the Pathogenesis of Kidney Diseases

Non-programmed cell death, known as necrosis induced by infection and injury, is one of two types of cell death. Programmed cell death refers to the elimination of damaged cells and maintenance of internal homeostasis. Programmed cell death mainly includes apoptosis, autophagy, ferroptosis, necroptosis, and pyroptosis (Table 1). Apoptosis, a type of cell death dependent on the caspases, is characterized by nuclear lysis, chromatin condensation, formation of apoptotic bodies, and cell shrinkage (Table 1). Apoptosis is likely a leading mechanism resulting in tubule cell and podocyte loss in acute and chronic kidney disease. z-VAD, a pan-caspase inhibitor, inhibited apoptosis of renal tubule cells and prevented inflammation and tissue injury in acute kidney injury (AKI). Caspase-3 knockout mice had less severe microvascular endothelial cell apoptosis and reduced renal fibrosis after ischemia-reperfusion (I/R) [1]. BAX/BAK double knockout improved renal function via inhibiting renal tubular apoptosis in mice [2]. Mice with genetic deletion or pharmacological inhibition of caspase-9 showed lower apoptosis by reduction of inflammation in acute kidney disease or renal fibrosis [3]. The core features of autophagy involve the formation of double-membraned vesicles, known as autophagosomes (Table 1). Autophagy precedes apoptosis as a first response to cellular damage; if failed in eliminating the damage, autophagy is blocked and apoptosis is induced. Autophagy was upregulated and played a renoprotective role in AKI [4]. It remains controversial as to the role of autophagy in kidney fibrosis. Many studies showed that autophagy promoted renal fibrosis. Pharmacological inhibitors of autophagy or selective deletion of ATG7 in proximal tubules reduced unilateral ureteral obstruction (UUO)-associated fibrosis [5]. The overexpression of WISP-1 increased the level of LC3-II and Beclin 1 and exacerbated renal fibrosis [6]. Contrary to the above description, several studies have also demonstrated anti-fibrosis effects of autophagy in the kidney. Deletion of LC3B and Beclin 1 in mice resulted in collagen deposition in the UUO model via further increased TGF-β expression [7]. Proximal tubular epithelial cell (TEC)-specific deletion of Atg5 observed severe interstitial fibrosis [8]. Deletion of Atg5 or Atg7 in the kidney epithelium resulted in CKD in mice, impairment of the autophagic process leads to progressive CKD [9]. Necroptosis shares a mechanistic similarity to apoptosis and bears a morphological resemblance to necrosis [10]. Necroptosis is characterized by RIPK3 activation by phosphorylation and the subsequent phosphorylation of MLKL (Table 1). Phosphorylated MLKL translocates to the plasma membrane and disrupts the integrity of the cell, allowing the release of cell contents [11]. Recent evidence reported that necroptosis is significantly implicated in the occurrence and development of renal diseases by activating RIPK1, RIPK3, and MLKL. Genetic deletion of RIPK3 in mice, catalytically inactive RIPK1, MLKL knockout mice, or treated with RIPK1 inhibitors, necrostatin-1, or Cpd-71, had alleviated AKI and improved renal function [12]. Inhibition of necroptosis attenuated renal injury via blockade of RIPK3 and was treated with necrostatin-1 in kidney fibrosis and chronic kidney disease [13]. Ferroptosis is a recently identified cell death mechanism characterized by massive lipid peroxidation, suppressed mainly by GPX4 and FSP1 (Table 1). Ferroptosis may be an early event driving the amplification of kidney injury through recruitment of inflammation and other forms of regulated necrosis. The ferroptosis inhibitor ferrostatin-1 improved renal function and reduced structural organ damage in folic acid (FA)-AKI [14]. Tonnus et al. [15] showed that the deletion of FSP1 or GPX4 improved the sensitivity of tubular ferroptosis in ischemia-reperfusion injury (IRI)-AKI mice. Zhou et al. [16] recently reported that polydatin enabled to attenuate the ferroptosis in cisplatin-induced AKI via regulating system Xc−/GSH/GPX4 pathway and inhibiting iron metabolism disorders. Pyroptosis is a hotspot in recent years, also defined as inflammatory cell death program. Compared with apoptosis, pyroptosis occurs more rapidly and is accompanied by destruction of cell membrane integrity and the release of proinflammatory factors (Table 1) [17]. Pyroptosis is characterized by swelling and rupture of cells, nuclear shrinkage, cell contents secretion, DNA staining positive, and significant proinflammatory response (Table 1) [18].

In the process of pyroptosis, nod-like receptors (NLRs) recognized the pathogen-associated molecular patterns and damaged-associated molecular patterns and induced the formation of the inflammasome. The inflammasome triggers activated caspase-1 and then cleaves GSDMD into two fragments (the N domain and the C domain). GSDMD-N fragment is dispensable for pyroptosis and then inserts into the cell membrane by binding with membrane lipids, phosphoinositides, and cardiolipin and perforates membrane pores (10∼20 nm in diameter), which is accompanied by the release of the cytokines, including interleukin-1β (IL-1β) and IL-18, into extracellular space [19]. Previous studies revealed pyroptosis played crucial roles in neurodegenerative diseases, cardiovascular diseases, atherosclerosis, rheumatoid arthritis, infectious diseases, tumors, and kidney diseases [20‒25]. The role of apoptosis and other cell death in kidney diseases has been widely studied. However, the relationship between pyroptosis and kidney diseases is not fully understood at present.

Pyroptosis is divided into canonical pathway (caspase-1-dependent) and noncanonical pathway (caspase-4, 5, 11-dependent) (Fig. 1). In canonical pathway, activated inflammasome triggered caspase-1, cleaved GSDMD, and induced downstream inflammatory responses [26]. In noncanonical pathway, inflammasome is dispensable, and pyroptosis is induced by lipopolysaccharide (LPS) on the surface of G⁻ bacteria by activating murine caspase-11 and its human ortholog caspase-4/5 [27]. Here, we overviewed recent advances in the mechanisms of pyroptosis in order to best explore potential therapies targeting pyroptosis in nephropathy.

The inflammasomes are the receptors/sensors of the innate immune system. The function of inflammasomes is to regulate the activation of caspase-1 and induce inflammatory responses in response to infectious microorganisms and molecules. NLRP3 is one member of the NLR protein families, which include about 22 members in humans and 34 members in mice [28]. NLRP3 inflammasome complex consists of NLRP3, the adapter molecule ASC, and the effector protein pro-caspase-1. ASC contains two domains: a pyrin domain (PYD) and a caspase activation and recruitment domain (CARD), which are essential for ASC coupling the upstream PRR to caspase-1 [29]. Assembly of NLRP3 inflammasome triggers proteolytic cleavage of pro-caspase-1 into active caspase-1, which then converts pro-IL-1β and pro-IL-18 into mature and biologically active cytokines IL-1β and IL-18, respectively [30].

NLRP3 inflammasome is one of the most deeply studied inflammasomes and is most strongly associated with uncontrolled inflammatory responses. The mechanisms of NLRP3 inflammasome complex activation mainly included ionic channel opening (K⁺ efflux, Cl⁻ efflux, Ca⁺ influx), lysosomal leakage, mtDNA, and mtROS released by mitochondrial dysfunctions in canonical inflammatory pathway [31]. Additionally, NLRP3 inflammasome was activated by Gram-negative but not Gram-positive bacteria in noncanonical pathway, suggesting a role for LPS in the pathway. LPS is delivered into the cytosol and activates caspase-11, which also drives pyroptosis through cleavage of GSDMD. The alternative NLRP3 inflammasome is activated in human monocytes in response to LPS [32]. In this pathway, K⁺ efflux is dispensable, and the molecules RIPK1, FADD, and caspase-8 are required.

The inflammasome has been linked to many inflammatory diseases, such as neurodegenerative diseases and metabolic disorders. Previous studies showed the inflammasome was core for inflammatory responses and crucial for pyroptosis occurrence in kidney diseases. For instance, inhibiting NLRP3 activation with inhibitors and silencing NLRP3 with siRNA or knockdown of caspase-1 alleviated ochratoxin A-induced renal fibrosis [33]. IL-22 alleviated renal fibrosis and proteinuria in diabetic nephropathy (DN) via inhibition of NLRP3 inflammasome [34]. Knockdown of C/EBPβ inhibited NLRP3 inflammasome-mediated pyroptosis by inactivating TFAM/RAGE pathway in AKI [35]. NLRP3 inflammasome played a significant role in renal diseases. Therefore, further understanding the activation mechanism of NLRP3 inflammasome is vital for the treatment of NLRP3 inflammasome-related diseases.

Pyroptosis was defined as programmed necrotic cell death mediated by gasdermins [36]. Gasdermin family mainly consists of 6 members: GSDMA, B, C, D, E, and pejvakin (PJVK). Except for PJVK (also called DFNB59), all members have a highly conserved N-terminal domain mediating pyroptosis [37]. Here, we focus on the two most deeply studied gasdermin members, GSDMD and GSDME, in pyroptosis. GSDMD, the executioner of pyroptosis, is the common substrate of caspase-1/4/5/11. GSDMD consists of two conserved domains: C-terminal inhibitory domain and N-terminal effector domain. The N-terminal of GSDMD is cytotoxic and forms pores via binding with lipid components in the plasma membrane, while the full-length structure of GSDMD is not cytotoxic. GSDMD was cleaved by mice caspase-1 and caspase-11 or human caspase-1/4/5, released the active form of GSDMD-N fragment, and oligomerized in the plasma membrane to generate pores, which induced pyroptosis by mediating the secretion of mature IL-1β and IL-18 [38]. Caspase-3 was regarded as the hallmark of apoptosis and was not involved in pyroptosis [39]. However, recent studies revealed caspase-3 converts noninflammatory apoptosis to pyroptosis via cleaving GSDMD [40]. In addition, the finding showed caspase-3 cleaved GSDME in GSDME-expressing cells, which then formed pores in the plasma membrane, triggering pyroptosis [41]. GSDME cleaved by caspase-3 plays a key role in cancer treatment and antitumor immunity. The finding demonstrated that GSDME switched caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis [42]. In this progression, apoptosis-related proteins were also activated at about the same time, but the progression of pyroptosis was faster. Therefore, the outcome shows as pyroptotic. Besides, GSDMC and GSDMD were cleaved by caspase-8 and induced pyroptosis [43, 44].

Caspase-1-dependent canonical pyroptotic death involves four major steps, namely, inflammasome assembly, the activation of pro-caspase-1, the cleavage of GSDMD, and the release of IL-1β and IL-18 [24]. Caspase family is divided into two groups, respectively: proapoptotic-relative members (caspase-2, 3, 6, 7, 8, 9, 10) and proinflammatory-relative members (caspase-1, 4, 5, 12) [45]. Caspase-1 is the best-described inflammatory caspase. Caspase-1, known as IL-1β-converting enzyme (ICE) and the effector protein of NLRP3 inflammasome, was located in the cytosol in the form of inactive pro-caspase-1. The PYD of NLRP3 binds to the PYD of the adapter protein ASC. ASC, composed of only a pyrin and a CARD domain, can recruit caspase-1 via CARD-CARD interactions [46]. The oligomerization of caspase-1 precursor protein induces its own proteolysis into activated caspase-1 [47]. Caspase-1 activation, considered to be an initiating factor for pyroptosis, is regulated by distinct inflammasomes. Activated caspase-1 processed precursor cytokines pro-IL-1β and pro-IL-18 into their bioactive forms, respectively. Mature IL-1β and IL-18 secreted into extracellular space participate in immune regulation [46]. In addition, AIM2, NLRC4, and NLRP1b activated caspase-1 by forming an inflammasome and recruiting ASC [48].

Noncanonical inflammatory pathway was activated by intracellular LPS derived from gram-negative bacteria (Fig. 1). Caspase-11 is the homologous protein of caspase-1. However, the heterogeneity between their sequences may have accounted for mediating two different pathways [49]. In noncanonical inflammasome pathway, in mice, caspase-11-mediated pyroptosis occurs by sensing directly intracellular LPS and binding to the lipid A moiety in LPS in macrophages, which is independent of caspase-1 activation [49]. Noncanonical inflammasome assembly in humans is accomplished similarly to its formation in mice [50]. Caspase-4/5/11 recognizes LPS in host cells via CARD domain, which triggers caspase-4/5/11 oligomerization and consequently activation of its proteolytic activity [50]. Activated caspase-4/5/11 regulated the secretion of mature IL-1β and IL-18 via NLRP3-ASC-caspase-1 pathway, but they are unable to directly cleave pro-IL-1β and pro-IL-18 [51]. Broz et al. [52] found caspase-11-induced caspase-1-independent cell death in the host with Salmonella infection. Activated caspase-11 induces the cleavage of the downstream of GSDMD, which triggers pyroptosis via the N-terminal of GSDMD, forming pores on the cell membrane [53]. Many studies have focused recently on the role of caspase-11 in kidney diseases. In 2018, Miao et al. [54] found caspase-11 was significantly elevated and mainly located in renal tubules in cisplatin-induced AKI. In addition, Miao et al. [24] in 2019 also demonstrated caspase-11 accelerated the progression of renal fibrosis via inducing caspase-1 activation and the maturation of inflammatory cytokines IL-1β and IL-18. Besides, caspase-11 aggravated I/R-induced AKI via the cleavage of panx1, facilitating ATP release and NLRP3 inflammasome activation [55].

AKI is pathologically characterized by sublethal and lethal damage of renal tubules. I/R injury, nephrotoxins (such as contrast, cisplatin), sepsis are the main causes of AKI. Both apoptosis and necrosis have been most studied in AKI, but the role of pyroptosis in AKI remains unclear.

I/R-induced AKI is a major clinical problem. Sublethal and/or lethal damage of RTECs is a typical pathological characteristic of AKI [56]. In 2022, the finding showed that RTEC-specific deletion of DUSP2 permits STAT1 hyperactivation and thereby promotes RTEC pyroptosis through transactivating GSDMD during AKI [56]. Endoplasmic reticulum (ER) stress is closely associated with pyroptosis in I/R-induced AKI (Fig. 2). CHOP, the biomarker of ER stress, triggered caspase-11-mediated caspase-1-dependent pyroptosis in I/R-induced AKI [57]. SIRT1 signaling pathway alleviated kidney injury induced by I/R through downregulating ER stress-mediated pyroptosis [58]. Besides, TLR4/PKC/gp91-mediated ER stress, apoptosis, autophagy, and pyroptosis signaling play an important role in LPS-induced AKI [59]. Oxidative stress is the primary pathogenesis of AKI. Recently, many studies have shown that the attenuation of ROS production induced by antioxidant pathways results in a reduction of renal pyroptosis (Fig. 2). Nrf2, which is a well-known transcription factor with an important role in cytoprotection, is activated by excessive ROS. Pang et al. [60] showed the level of pyroptosis was obviously increased in H/R-induced HK-2 cells after knockdown of Nrf2. The inhibition of miR-92a-3p alleviated oxidative stress and pyroptosis of TECs by targeting Nrf1 in renal I/R [61]. In addition, HO-1, an inducible antioxidant enzyme, inhibited pyroptosis via reducing oxidative stress, which can alleviate endotoxin-induced AKI by PINK1 [62]. Subsequently, the latest study revealed TRIM8 downregulation inhibited PI3K/AKT pathway-mediated oxidative stress, thus blunting pyroptosis in H/R-induced HK-2 cells [63]. IRI is an inevitable consequence of renal transplantation and a major determinant of graft survival. In 2018, Zhao et al. [64] verified that blocking the histone-TLR4 pathway prevented the hepatic pyroptosis caused by renal allograft IRI.

Drug-related acute TEC injury is the most common cause of AKI. Contrast-induced AKI (CI-AKI) is a serious complication in patients after administration of iodinated contrast media. Pyroptosis was closely associated with CI-AKI, in which the expression of pyroptosis-related proteins NLRP3 and pro-caspase-1 got a marked increase [65]. In 2018, Zhang et al. [66] reported that CI-AKI was abrogated in caspase-11-deficient mice, and deletion of caspase-11 TECs reduced GSDMD cleavage. Acetylbritannilactone attenuated CI-AKI through its anti-pyroptosis effects [67]. αKlotho reduced contrast-induced pyroptosis of TECs by limiting NLRP3 inflammasome activation [68]. Both contrast and cisplatin in clinic were considered to be the main nephrotoxins-induced AKI. In 2019, Miao et al. [24] found that disruption of caspase-11 attenuated cisplatin-induced AKI via reducing the cleavage of GSDMD and the production of IL-18. The similar results have been proved in primary proximal tubule cells. Afterward, Li et al. [69] reported that the overexpression of GSDMD-N fragment in TECs or mice in the kidney was more susceptible to cisplatin-induced AKI than control mice. In 2021, Jiang et al. [70] discovered that vitamin D/VDR could partially alleviate AKI by inhibiting NLRP3/caspase-1/GSDMD pyroptosis. Of note, GSDME is a newly identified mediator of pyroptosis via the cleavage of caspase-3. In 2021, Xia et al. [71] found that GSDME deletion ameliorated cisplatin-induced AKI. GSDME-N promoted cisplatin-induced cell injury and pyroptosis in human TECs. High doses of FA-induced TEC damage are also a common model of AKI. Previous results showed ibudilast exerted an anti-pyroptosis effect on FA-induced AKI. The deposition of intratubular crystals was thought to be the primary cause of AKI. Approximately 80% of renal calculi are initiated by the deposition of calcium oxalate (CaOx) crystals. Pyroptosis mediated by NLRP3 serves a critical role in the cytotoxicity of CaOx crystals in nephropathy. CaOx crystals activate IL-1β secretion in murine kidneys through a pathway including NLRP3, ASC, and caspase-1 [72]. CP-456,773, a specific inhibitor of the NLRP3 inflammasome, strongly alleviated kidney fibrosis in crystal nephropathy [73]. H3 relaxin inhibits GSDMD synthesis and pyroptosis by regulating NLRP3 inflammasome activation in CaOx crystal-induced TEC damage [74]. The pyroptosis-related protein expression levels of IL-1β and GSDMD were obviously upregulated in CaOx crystal-induced injury [75]. Recent research showed miR-141-3p overexpression alleviated CaOx crystal-induced RTEC injury by targeting NLRP3-mediated pyroptosis [76]. Briefly, pyroptosis is involved in nephrotoxic drug-related AKI.

AKI is a complication of sepsis. LPS is used to induce AKI by intraperitoneal administration. Pyroptosis in TECs is a key event during septic AKI. Caspase-11 and GSDMD were elevated in LPS-induced sepsis, thus aggravating obviously AKI by regulating pyroptosis [77, 78]. Recent studies revealed that many important signaling molecules participated in sepsis-induced AKI via regulating pyroptosis. For example, knockdown of DLX6-AS1 upregulated miR-223-3p and inhibited the expression of NLRP3, which alleviated LPS-induced pyroptosis in HK-2 cells [79]. In 2020, Dai et al. [35] demonstrated C/EBPβ and TFAM promoted AKI by activating NLRP3-mediated pyroptosis. Inhibition of TNF-α/HMGB1 inflammation signaling blunt the process of pyroptosis, thus relieving AKI [80]. Li et al. [62] found HO-1/PINK pathway attenuated LPS-induced AKI by inhibition of pyroptosis. M1 and M2 macrophages were considered to have opposite influence on the pyroptosis of TECs. Juan et al. [81] revealed M1 exosomes promoted cell pyroptosis while M2 exosomes inhibited cell pyroptosis, and M2-derived miR-93-5p protected against AKI through regulating TXNIP. In 2021, Deng et al. [82] demonstrated that lncRNA MEG3 activated pyroptosis by regulating the miR-18a-3p/GSDMD pathway in LPS-induced AKI. Wang et al. [83] found recently ROCK1 regulated sepsis-induced AKI via TLR2-mediated ERS/pyroptosis axis. Zhang et al. [84] found IRF2-regulated caspase-4/11-mediated noncanonical pyroptosis pathway in sepsis-related AKI. In 2022, Sun et al. [85] demonstrated that USF2 knockdown downregulated THBS1 to reduce pyroptosis and further ameliorate septic AKI. Transcription factor ETS1 regulated the transcript of NLRP3, which blunted the renal tubular epithelial pyroptosis [86]. The latest research confirmed that silencing MIF alleviated NLRP3 inflammasome-mediated pyroptosis in sepsis-induced AKI [87].

More recently, researchers found that some drugs attenuated AKI by inhibition of pyroptosis. β-Hydroxybutyrate is the most abundant ketone body and possesses a protective activity in kidney diseases. For example, β-Hydroxybutyrate effectively mitigated podocyte senescence via targeting the GSK3β and Nrf2 in diabetic kidney disease and ameliorated renal cyst growth in polycystic kidney disease [88, 89]. In 2019, the research showed β-Hydroxybutyrate attenuates renal injury through FOXO3-mediated anti-pyroptotic effects [90]. Salvianolic acid B was examined to reverse the upregulation of pyroptosis-related proteins in I/R-induced AKI via activating Nrf2 [60]. Thymoquinone can decrease the expression of NLRP3 and caspase-1 proteins in sepsis-induced AKI [91]. H₂S prevented I/R-induced AKI via suppressing the NLRP3/caspase-1 axis [92]. Cholecalciferol inhibited GSDMD-mediated pyroptosis, which effectively improved renal function in I/R-induced AKI [93]. These studies show pyroptosis has become a new therapeutic target for the treatment of AKI.

Renal fibrosis is the end point of almost all progressive chronic kidney diseases. The main mechanisms of renal fibrosis were associated with inflammatory responses, fibroblast accumulation, tubular cell loss, and rarefaction of the peritubular microvasculature [94]. Ureteral obstruction is one of the most common problems in obstructive nephropathy. If ureteral obstruction cannot be relieved in time, it will lead to renal fibrosis and loss of renal function. Inflammation is always considered an initiator of renal fibrosis [95].

It is a hotly debated issue about the role of pyroptosis in renal fibrosis. In 2012, Chung et al. [96] found Nrf2 signaling pathway effectively suppressed caspase-1/IL-1β/pyroptosis in UUO mice. GSDME deletion had potential protective effects against fibrosis and inflammation in kidneys treated with 5/6 nephrectomy [97]. Besides, Li et al. [98] identified TNF-α/caspase-3/GSDME signaling-mediated pyroptosis in the initiation of renal fibrosis via triggering the release of HMGB1 and inflammasome activation. Interestingly, this study verified that caspase-3/GSDME-mediated pyroptosis in renal tubules, but not infiltrating immune cells, predominantly accelerated the progression of renal fibrosis. Additionally, pyroptosis in mesangial cells mediated by NLRP3/caspase-1/IL-1β pathway participated in UUO-induced renal fibrosis [99]. The latest research revealed Cx43-mediated peritubular macrophage pyroptosis, thus inducing acceleration of renal fibrosis [100].

Few studies have revealed that drugs targeting pyroptosis significantly prevent the progression of renal fibrosis. For example, sulforaphane activating Nrf2 signaling ameliorated UUO-induced renal damage by depressing pyroptosis [96]. Disulfiram, a drug used to treat alcohol addiction and a pore-formation inhibitor of GSDMD, alleviated inflammation and fibrosis in a rat UUO model by inhibiting GSDMD cleavage and pyroptosis [101]. Huoxue Jiedu Huayu formula prevented the development of pyroptosis by downregulating NLRP3/caspase-1/IL-1β pathway in UUO rats [102]. Suyin Detoxification Granule inhibited NLRP3-mediated pyroptosis during renal fibrosis [103]. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, alleviated renal fibrosis by reducing pyroptosis-related cytokines [104]. Collectively, these results uncovered pyroptosis, as a novel mechanism, and would provide valuable therapeutic insights for the treatment of renal fibrosis.

DN is characterized by sterile inflammation. Pyroptosis, a newly discovered cell death pathway, participated in DN. Here, we look forward to communicating the latest research progress in pyroptosis and its development in the field of DN. Tian et al. [105] showed that A1 adenosine receptor played a protective role in proximal tubular megalin loss-associated albuminuria by inhibiting the pyroptosis-related caspase-1/IL-18 signaling in DN. In 2019, Wang et al. [106] reported that GSDMD-related pyroptosis was activated in diabetic mice model and HK-2 cells treated with high glucose (HG). This study revealed increased expression of TLR4, cleaved caspase-1, GSDMD, and secretion of IL-1β were partly reversed by TLR4 and NF-κB inhibitors. In 2020, Ke et al. [107] unveiled that ER stress-related factor IRE1α upregulated TXINP by degrading miR-200a, activated the NLRP3/TXNIP pathway-mediated pyroptosis, and aggravated kidney damage.

Long noncoding RNAs (LncRNAs) participated in DN by interacting with microRNAs (miRNAs) (Fig. 3). In 2017, Li et al. [108] found LncRNA MALAT1 reversed the effect of miR-23c on the downregulation of its target ELAVL1, which attenuated kidney injury via preventing pyroptosis of TECs. In addition, Liu et al. [109] revealed that LncRNA MALAT1 downregulation inhibited HG-induced pyroptosis of HK-2 cells by upregulating the level of miR-30c. In 2021, Zuo et al. [110] also found LncRNA MALAT1 was positively related to pyroptosis in podocytes treated with HG. The level of LncRNA GAS5 was negatively correlated with oxidative stress and pyroptosis in TECs treated with HG by suppressing the expression of miR-452-5p [111]. But the expression of LncRNA KCNQ1OT1 obtained fully contradictory roles in HG-induced TECs via promoting the expression of miR-506-3p [112]. LncRNA NEAT1 upregulation promoted pyroptosis in DN by via the target gene MiR-34c [113]. LncRNA NEAT2 was also positively correlated to pyroptosis in HK-2 cells under HG treatment [114]. LncRNA ANRIL activated pyroptosis via directly bounding miR-497 to disinhibit TXNIP expression in DN [115]. The latest research showed that knockdown of lncRNA XIST alleviated DN by inhibiting NLRP3/caspase-1-mediated pyroptosis [116]. Moreover, circular RNAs also played a significant role in DN. The study showed that knockdown of circACTR2 significantly inhibited pyroptosis in HG-induced TECs [117].

Previous studies have demonstrated that many drugs against pyroptosis obviously alleviated DN. Punicalagin attenuated DN by inhibiting TXNIP/NLRP3 axis-mediated pyroptosis [118]. In 2019, Gu et al. [119] revealed that sodium butyrate dramatically inhibited caspase-1-GSDMD canonical pyroptosis in renal glomerular endothelial cells. Geniposide effectively blocked pyroptosis, which attenuated DN, and its mechanism might be related to APMK/SIRT1/NF-κB pathway [120]. Tangshen Formula protected tubular epithelium from pyroptosis by regulating the TXNIP-NLRP3-GSDMD axis [121]. Han et al. [122] found hirudin ameliorated GSDMD-mediated pyroptosis by inhibiting irf2, which prevented the progression of DN. Carnosine alleviated podocyte injury in DN by inhibiting caspase-1-mediated pyroptosis [123]. In 2022, Wang et al. [124] demonstrated that fucoidan significantly inhibited NLRP3 inflammasome-mediated podocyte pyroptosis in the diabetic kidney. Qu et al. [125] substantiated that pyrroloquinoline quinone blunted pyroptosis activation in DN-related renal fibrosis. The latest research revealed that N-acetylmannosamine, as a sialic acid precursor, reduced podocyte pyroptosis through inhibiting ROS/NLRP3 signaling pathway in a diabetic kidney injury model [126]. The considerable evidence has confirmed pyroptosis may be a target for the treatment in DN.

Renal cell carcinomas (RCCs) account for 80∼90% of all primary renal neoplasms [127]. Emerging research has substantiated that pyroptosis is closely related to the initiation and development of RCC. Pyroptosis-related genes have a complex regulatory system in RCC via influencing immunotherapy, clinical and pathological characteristics, and prognosis [128].

The tumor microenvironment has the critical regulatory effect on tumor progression [129]. The pyroptosis-related risk model effectively reflected the status of the immune microenvironment for RCC patients [130]. Sun et al. [131] found that the expression level of pyroptosis-related genes was upregulated and positively correlated with the infiltrating levels of immune cells in RCC. GSDM family directly or indirectly affects the development of RCC. In 2022, Yao et al. [132] revealed the mRNA levels of GSDMA/B/D/E were positively correlated with tumor grade and may be potential biomarkers for the diagnosis and prognosis of RCC. GSDMD, a key factor in pyroptosis, was highly expressed and may be used as a prognostic marker in RCC [133]. Interestingly, the study showed GSDMD prevented tumor in the early stage. Conversely, it became a risk factor in the late stage of RCC. In addition, GSDMD in male patients was a risk factor for RCC but a protective factor in female patients [133]. Xia et al. [134] also considered that pyroptosis played a dual role during tumor progression. Cui et al. [135] found that GSDMB was markedly upregulated and related to the high pathologic stage. Upregulation of GSDMB was closely related to immune infiltrates and a poorer prognosis in RCC [131, 135]. Previous studies revealed pyroptosis regulators participated in the development and prognoses of RCC. Zhang et al. [136] considered AIM2 to be the most important immune-related pyroptosis regulator. In this study, the research revealed that AIM2 was related to the immune activation pathway and significantly elevated in tumor tissues. In addition, Lin et al. [137] found AIM2 and DFNB59 were independent prognostic factors, patients with high expression of which had a poor prognosis. Specific pyroptosis-associated lncRNA signature may help predict the prognosis of RCC [138]. Downregulation of BRD4 suppressed proliferation and epithelial-mesenchymal transition by inhibiting the NF-κB/NLRP3/caspase-1-mediated pyroptosis in RCC [139]. Additionally, as a type of death, pyroptosis suppresses tumor progression [134]. But there are few relevant studies in RCC. In conclusion, pyroptosis may be involved in targeted therapies for patients with RCC.

Many studies have confirmed that various drugs or small molecular inhibitors alleviate renal damage by regulating pyroptosis. Pyroptosis is induced by activation of inflammasome sensors. To date, several members of the PRRs, such as NLRP3, NLRC4, AIM2, can form inflammasomes [140]. The inhibition and activation of PRRs are referred to as new treatments for pyroptosis. For example, ibudilast, a TLR4 antagonist, reduced the levels of both NLRP3 and caspase-1, IL-1β, IL-18, and GSDMD cleavage [141]. Thus, this study substantiates that ibudilast has a protective effect on FA-induced AKI in mice by reducing pyroptosis and inflammation. In addition, Wang et al. [106] revealed that TAK-242, an inhibitor of TLR4, also reduced the expression of pyroptosis-related proteins and the secretion of inflammatory cytokines, which blunt the progression of tubular injury in diabetic kidney disease. The TLR2 inhibitor, C29, suppressed ERS-mediated cell pyroptosis in HK-2 cells under LPS treatment [83]. The inhibitor MCC950 of NLRP3 ameliorated OTA-induced renal fibrosis via the inhibition of pyroptosis in Madin-Darby canine kidney cells [33]. Besides, MCC950 was substantiated to effectively blunt the pyroptosis of TECs under chronic intermittent hypoxia treatment [142]. Another selective and direct NLRP3 inhibitor, CY-09, also arrested the progression of renal fibrosis by preventing the activation of the NLRP3/ASC/caspase-1 signaling pathway in HK-2 cells treated BSA [103].

Pyroptosis is a caspase-1-dependent proinflammatory form of programmed cell death. The caspase-1 inhibitors have a marked renoprotective effect by inhibiting pyroptosis. For example, in 2019, this study found HG-induced NF-κB/IκB-α signaling pathway was reversed by AC-YVAD-CMK, which inhibited pyroptosis and ameliorated sepsis-induced AKI via effectively blocking the cleavage of pro-IL-1β and pro-IL-18 and inflammatory response [119]. Chou et al. [143] also found YVAD, in human TECs, blunts ER stress via inhibiting caspase-1- and NLRP3 inflammasome-dependent pyroptosis. In addition, pyroptosis was inhibited by AC-YVAD-CMK in sepsis-induced AKI [144]. In HIV-associated nephropathy, the caspase-1 inhibitor, glyburide and tempol decreased HIV-induced caspase-1, cleaved caspase-1 p20, and IL-1β expression in podocytes [145]. Moreover, Z-YVAD-FMK, as a caspase-1 inhibitor, inhibited duck renal TEC pyroptosis, which relieved Cd-induced nephrotoxicity [146]. Z-YVAD-FMK efficaciously also reduced pyroptosis effects on BD-induced kidney injury [147]. In 2022, recent results showed the selective caspase-1 inhibitor VX-765 downregulated pyroptosis-associated protein in glucose-induced TCEs and diabetic mice [148]. These results demonstrated that inhibitors of caspase-1 were a promising therapeutic opportunity for kidney diseases.

Gasdermins was discovered to form a pore and act as the effector for pyroptosis. Recently, a number of studies have showed that blocking gasdermin-mediated pyroptosis attenuates markedly kidney injury. Han et al. [122] revealed hirudin, a thrombin inhibitor, deregulated the expression of GSDMD by inhibiting IRF2, leading to the improvement of kidney function in DN. Ibudilast reduced the levels of both inflammasome markers (NLRP3) and pyroptosis-related proteins (caspase-1, IL-1β, IL-18, and GSDMD cleavage) in FA-induced AKI [141]. Vitexin, a flavonoid monomer, also inhibited pyroptosis activation by decreasing the level of GSDMD and exerted protective effects against nephrolithiasis [75]. In 2021, Zhang et al. [101] confirmed that the specific inhibitor of GSDMD, Disulfiram, blunted inflammatory response and fibrosis in UUO rats by inhibiting GSDMD splicing and pyroptosis. Additionally, the GSDMEb-derived peptide inhibitor, Ac-FEID-CMK, effectively attenuated the proximal renal tubular damage in LPS-induced AKI [77]. We reviewed the studies associated with the treatment for kidney diseases with a view to pyroptosis pathways, and the overview of these potential renoprotective drugs is shown in Table 2.

In our review, we have mainly discussed the role of pyroptosis in AKI, renal fibrosis, diabetic kidney injury, RCC, and the therapeutic effects of targeting pyroptosis in the first three diseases. We consider pyroptosis is closely related to kidney disease, and inhibition of pyroptosis may be a potential therapeutic strategy for various nephropathies (Fig. 4). With further research, the role of pyroptosis in other renal diseases has also begun to be reported. For example, pyroptosis also participates in the regulation of hyperuricemic nephropathy, lupus nephritis, metabolic-associated kidney diseases, and glomeruli disease. However, the detailed role and mechanism require further investigation. Most of the studies we summarized originated from experimental animals and cells, lack of clinical cases. Up to date, multiple mechanisms are involved in pyroptosis, including autophagy, mitochondrial dysfunction, oxidative stress, and ER stress. The pathogenesis of renal diseases is complicated. The specific regulatory network still needs additional research. Additionally, in our review, the relationship between pyroptosis and RCC has been discussed. We confirm that pyroptosis promotes the progression of RCC via regulating tumor cell proliferation, tumor microenvironment immunotherapy, prognosis. But pyroptosis has dual effects on RCC. The evidence related to pyroptosis inhibiting RCC is insufficient. Besides, we do not review the treatment for RCC. Collectively, these research uncover pyroptosis, as a novel mechanism, and will provide valuable therapeutic insights for the treatment of renal diseases.

The authors declare that they have no conflicts of interest.

No funding agency granted the present study.

Zhuanli Zhou performed data collection and analysis and wrote the manuscript. Qin Li contributed to the study conception and design. All authors approved the final manuscript.