Pyroptosis: A New Frontier in Kidney Diseases Part 2

4.4. Inflflammatory Kidney Disease. Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE). Clinically, approximately 50% of patients may have LN complications. The pathogenesis of LN is mainly related to inflammatory cell infiltration, activation of blood coagulation factor, and the release of inflammatory mediators caused by the deposition of immune complexes in the glomeruli. Patients with renal interstitial disease and the vascular disease usually experience much more severe kidney injury and poor prognosis.

Previously, the inflammatory mediator IL-18 was assumed to play an important role in LN. The NLRP3- ASC-caspase-1 signaling pathway has played a crucial part in kidney injury of SLE [79, 80]. The role of P2X7 in the noncanonical pyroptosis pathway has been proven to be related to the activation of caspase-1. In 2013, Zhao et al. [81] found that inhibition of the P2X7/NLRP3/caspase-1 signaling pathway effectively improved LN. A detailed study performed in 2017 confirmed that the inflammatory body NLRP3 was activated in patients and mice with LN, leading to Sertoli cell injury and severe albuminuria [82]. These results suggest the significance of the NLRP3 inflammatory body in LN. Piperine was found to alleviate LN by inhibiting the SLE mouse model and human near-end renal tubular epithelial cell pyroptosis, suggesting a possible role of pyroptosis in the progression of LN [83]. During the occurrence and progression of LN, the relationship between NLRP3 and pyroptosis is not clear. Whether NLRP3 cleaves SGDMD, a specific substrate for pyroptosis, also remains to be studied.

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IgA nephropathy (IgAN) is the most frequently seen primary glomerular disease, which means mainly IgA or IgA deposition at the mesangial region of glomeruli, and is accompanied by the presence or absence of other IgAs. It is estimated that 20%–40% of patients with IgAN will develop end-stage kidney diseases in 20 years [84]. Therefore, an investigation into the pathogenesis and progressive factors of IgA kidney disease may provide important information for disease treatment.

A study performed in 1997 reported the participation of the inflammatory medium IL-1 in the progression of IgAN, suggesting the important role of inflammation in IgAN [85]. It was recently reported that the expression of NLRP3 was significantly increased in kidney tubules of patients with IgAN [86, 87].

4.5. Other. At present, the occurrence and progression of many kidney diseases are related to pyroptosis. However, as it is not well studied, this has not been confirmed. Calcium oxalate (CaOx) nephropathy is caused mainly by the excessive accumulation of CaOx in the kidney, eventually leading to end-stage kidney disease. It was found that CaOx crystals could initiate IL-1β-dependent innate immunity by activating the NLRP3/ASC/caspase-1 signaling pathway of renal mononuclear phagocytes, causing mouse renal tubular injury and promoting the progression of CaOx nephropathy [88, 89]. Similarly, NLRP3 accelerated glomerular sclerosis in a CaOx nephropathy mouse model and led to progressive renal function failure by mediating an inflammatory reaction [90]. Meanwhile, the long-coding RNA LINC00339 was proven to induce renal tubular epithelial cell pyroptosis in patients with CaOx nephropathy by activating NLRP3 via miR-22-3p [91]. Multiple complications can occur in the early stage following kidney transplantation. Further, it has been shown that kidney transplantation could lead to kidney inflammation and far-end liver injury in rats. The markers related to pyroptosis increased markedly, but the correlation between complications resulting from kidney transplantation and pyroptosis needs further investigation [92]. The pathophysiological mechanisms of HIV and HIV-related kidney disease and particulate-induced kidney injury are also closely related to pyroptosis [93, 94]. These findings may provide a theoretical rationale for the discovery of new therapeutic targets and the physiopathological alterations in various kidney diseases.

5. Potential Medicines for Pyroptosis in Kidney Diseases

Within the studies concerning pyroptosis in the field of kidney diseases, several have focused on proteins related to the pyroptosis signaling pathway, that is, NLRP3, caspase-1, and the inhibitor or activator of GSDMD (Table 2). Quercetin, curcumin, and allopurinol were all found to exert anti-hyperuricemia and antihyperlipidemic functions and to reduce the release of inflammatory factors by inhibiting the activation of the inflammatory body NLRP3 in renal cells, thereby delaying the progression of DKD [95, 96]. It was also found that CP-456,773, a specific inhibitor of NLRP3, could delay the progression of mouse renal fibrosis owing to its early-stage inhibitory effect [97]. A recent study showed that artemisinin, an anti-inflammatory medicine, could alleviate rat renal tubule interstitial fibrosis by downregulating NLRP3 [98]. Three reagents targeting inflammatory kidney diseases have been found to directly inhibit the activation of NLRP3. Epigallocatechin-3-gallate (EGCG) and Bay11-7082 could largely mitigate the pathological changes of lupus nephropathy, and icariin, a flflavonoid from Chinese herbal medicine, Herba epimedium, effectively resists the inflammatory reaction in rats with IgAN [99–101]. In addition, some medicines indirectly inhibit the activation of NLRP3. Mdivi-1, dynamics-related protein 1 (DRP1), alleviated the symptoms of AKI mice by protecting mitochondrial function and inhibiting the activation of NLRP3 [102]. In addition, piperine significantly inhibited the activation of the NLRP3 inflammatory body and reduced the release of proinflammatory cytokines and mouse renal tubule pyroptosis by targeting AMPK to inhibit the development of LN [83]. Zhen-wutang is a well-known Chinese herbal medicine formula that inhibits the activation of NLRP3 and delays the reduction of renal function in IgAN rats by enhancing the secretion of renal exosomes [103].

Caspase-1 is a crucial link in the pyroptosis pathway; that is, the inhibitor of caspase-1 also inhibits the occurrence and progression of pyroptosis. Results showed that the downregulation of β-hydroxybutyrate and the expression of proinflammatory cytokines could alleviate pathological injury in AKI mice by inhibiting pyroptosis [104]. Mizoribine could also inhibit the inflammatory reaction in the kidney of renal fibrosis rats by inhibiting caspase-1 and alleviating the symptoms of hypertension [105].

As a specific substrate of pyroptosis, GSDMD is a key target for the regulation of renal pyroptosis. It was found that sodium butyrate alleviated the pyroptosis of glomerular vascular endothelial cells in DKD mice, providing a new target for the treatment of DKD [69]. Recent studies reported that Catalpol and Geniposide could alleviate the symptoms of DKD mice by inhibiting pyroptosis-related proteins, such as GSDMD and GSDMD-N. Of course, there are many potential medicines for kidney diseases by resisting pyroptosis [107, 108]. Riboflavin is considered an anti-inflammatory vitamin because of its antioxidant activity. Riboflflavin was found to delay pyroptosis and the release of IL-1β and IL-18 by inhibiting the activation of AIM2 and other inflammasomes. At present, studies concerning AIM2 inhibitors and pyroptosis are limited to cancer. Whether AIM2 inhibitors could function by inhibiting pyroptosis requires further investigation. Thus, more research on the topic is highly encouraged [108]. Overall, the present studies have their own limitations and require further confirmation.

6. Prospects and Summary

In summary, pyroptosis is mainly regulated by the caspase-1- a mediated canonical pathway and the caspase-4/5/11-mediated noncanonical pathway. The occurrence and progression of kidney diseases are more or less related to pyroptosis, and the inflammatory body NLRP3 is the most well-studied. This review examines the significance of pyroptosis in the pathogenesis of acute kidney injury, diabetic kidney, renal fibrosis, and inflammatory kidney disease. The role of pyroptosis as a key target for the treatment of kidney diseases is also highlighted. However, many problems remain to be addressed in the body of research.

At present, the study of pyroptosis is still in its infancy; there are many unanswered questions. For example, although the caspase protein family plays a crucial role in pyroptosis, irrespective of the canonical and noncanonical pathways, they are also the key proteins regulating the middle and late stages of apoptosis. There, when is the relationship between pyroptosis and apoptosis? Is pyroptosis an independent mode of cell death, or is it accompanied by other modes of cell death? Inflammation is a key process mediating pyroptosis, and oxidative stress is a frequently observed factor in inflammatory reactions. Can oxidative stress directly mediate pyroptosis? Studies on pyroptosis have concentrated mainly on two marker proteins, GSDMD and GSDME. Many studies have tended to expose the NT terminals of these two proteins and investigated oligomer-triggered pyroptosis. However, no study has ever reported free NT terminal-mediated pyroptosis. Such questions still need to be proven by a lot of studies.

Pyroptosis is actually a double-edged sword. When pyroptosis occurs in normal cells of kidney tissues, that is, Sertoli cells and renal tubular epithelial cells, many kidney-related diseases will occur. A majority of studies related to pyroptosis and kidney diseases have focused on this aspect. Meanwhile, moderate pyroptosis is an important immune response of the body that plays a very important role in resisting infection and endogenous risk factors. For example, will the removal of injured cells or fibroblasts in kidney tissues through pyroptosis alleviate the degree of kidney-related diseases? Few studies have ever addressed this issue. Therefore, further study is required to confirm this assumption.

At present, many medicines have been found to function by regulating the pyroptosis pathway. However, studies have largely focused on the field of cancer treatment. The research and development of medicines for the treatment of kidney-related diseases are ongoing. In the future, the medicines targeting pyroptosis for the treatment of another disease can be tested on kidney-related diseases, and novel medicines for the treatment of kidney-related diseases can be designed to target pyroptosis. This will provide a much better direction for the development of medication for kidney-related diseases.

Abbreviations

AIM2: Absence of melanoma 2

AKI: Acute kidney injury

AMPK: Adenosine 5′-monophosphate- (AMP-) activated protein kinase

ASC: Apoptosis-associated speck-like protein containing a CARD

ATP: Adenosine triphosphate

box: Zinc finger domain 

CaOx: Calcium oxalate 

CARD: Caspase activation and recruitment domain 

CC: A coiled-coil domain 

CHOP: C/EBP homologous protein

CKD: Chronic kidney disease 

DAMPs: Damage-associated molecular patterns 

DN: Diabetic nephropathy 

DNA: Deoxyribonucleic acid 

DRP1: Dynamics-related protein 1 

EGCG: Epigallocatechin-3-gallate 

ESRD: End-stage renal disease

GSDMD: Gasdermin D 

GSDME: Gasdermin E 

HIV: Human immunodeficiency virus 

HMGB1: High-mobility group box 1 protein 

IgAN: IgA nephropathy 

IL-1β: Interleukin-1β 

IL-18: Interleukin-18 

IRI: Ischemia-reperfusion injury 

LN: Lupus nephritis 

lncRNAs: Long noncoding 

RNAs LPS: Lipopolysaccharide 

LRRs: Leucine-rich repeats 

LT: Anthrax lethal toxin

MALAT1: Metastasis-associated lung adenocarcinoma transcript 1

miR: MicroRNA 

MLKL: Mixed lineage kinase domain-like protein 

NAIP: NLR family, apoptosis inhibitory protein 

NCCD: Nomenclature Committee on Cell Death 

NEAT1: lncRNA-Neat 1

NLR: Nucleotide-binding domain, leucine-rich repeat-containing

NLRC4: NLR family, CARD-containing 4 

NLRP1: NLR family, PYRIN domain-containing 1 

NLRP3: NLR family, PYRIN domain-containing 3 

NLRP6: NLR family, PYRIN domain-containing 6 

NLRP9: NLR family, PYRIN domain-containing 9

NOD/NACHT: Nucleotide-binding oligomerization domain

P2X7: Purinergic receptor P2X 

PAMPs: Pathogen-associated molecular patterns 

PARP: ADP-ribose polymerase 

PI: Propidium iodide 

PYD: Pyrin domain 

PYHIN: PYRIN and HIN-200 domain-containing 

RNA: Ribonucleic acid 

SLE: Systemic lupus erythematosus 

T3SS: Bacterial type III secretion system 

TLR-4: Toll-like receptor 4 

TUNEL: TdT-mediated dUTP nick-end labeling 

UUO: Unilateral ureteral occlusion.

Data Availability

The data used to support the finding of this study are available from the corresponding author upon request.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Authors’ Contributions

Ke-jia Zhang and Qi Wu drafted and proofed the manuscript. Yao Zhou edited the manuscript. All authors shave agreed on the submission and publication of this work. Ke-jia Zhang and Qi Wu contributed equally to this work and should be considered to-first authors.

Acknowledgments

This study was sponsored by the National Natural Science Foundation of China (Grant No. 82004107) and the Outstanding Talent Research Funding of Xuzhou Medical University (Grant Nos. D2019005 and D2019022).

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