Loss of NLRP6 expression increases the severity of acute kidney injury

Abstract

Background Nlrp6 is a nucleotide-binding oligomerization domain-like receptor (NLR) that forms atypical inflammasomes. Nlrp6 modulates the gut epithelium interaction with the microbiota. However, the expression and function of Nlrp6 in the kidney, a sterile environment, have not been characterized. We explored the role of Nlrp6 in acute kidney injury (AKI). Methods In a transcriptomics array of murine nephrotoxic AKI, Nlrp6 and Naip3 were the only significantly downregulated NLR genes. The functional implications of Nlrp6 downregulation were explored in mice and in cultured murine tubular cells. Results Nlrp6 was expressed by healthy murine and human kidney tubular epithelium, and expression was reduced during human kidney injury or murine nephrotoxic AKI induced by cisplatin or a folic acid overdose. Genetic Nlrp6 deficiency resulted in upregulation of kidney extracellular signal–regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) phosphorylation and more severe AKI and kidney inflammation. In cultured tubular cells, Nlrp6 downregulation induced by specific small interfering RNA resulted in upregulation of ERK1/2 and p38 phosphorylation and chemokine messenger RNA expression and downregulation of the nephroprotective gene Klotho. MAPK inhibition prevented the inflammatory response in Nlrp6-deficient cells. Conclusion Nlrp6 dampens sterile inflammation and has a nephroprotective role during nephrotoxic kidney injury through suppression of MAP kinase activation.

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

“…PGC-1α is encoded by the PPARGC1A gene and belongs to the PGC-1 family, also composed of PGC-1β (encoded by PPARGC1B), which contributes to maintain basal mitochondrial function, and PRC (PGC-1-related coactivator, encoded by PPRC1), which appears to be restricted to regulating mitochondrial biogenesis in proliferating cells [24] ( Figure 1A). While there is abundant literature on PGC-1α and kidney disease, as discussed below, much less is known about the role of PGC-1β and PRC in kidney disease, despite the fact that transcriptomic studies have identified them as differentially expressed during experimental AKI [25][26][27] (Figure 1B). [28].…”

The NLRP6 inflammasome

“…In the lung, Nlrp6 ‐deficient mice are more resistant to pulmonary Staphylococcus aureus infection compared with WT counterparts, and this protective effect is mediated by enhanced neutrophil recruitment and neutrophil‐associated bacterial clearance following infection 28 . Nlrp6 is also expressed in the tubular epithelium of healthy murine and human kidneys, and its expression is reduced upon acute kidney injury induced by folate acid or cisplatin overdose, in both human or mouse models 62 . Furthermore, deficiency of Nlrp6 in mice aggravates the severity of nephrotoxic acute kidney injury, characterized by enhanced apoptotic and pro‐inflammatory responses in the tubular cells, suggesting a nephroprotective role of NLRP6 in acute kidney injury 62 .…”

“…Nlrp6 is also expressed in the tubular epithelium of healthy murine and human kidneys, and its expression is reduced upon acute kidney injury induced by folate acid or cisplatin overdose, in both human or mouse models 62 . Furthermore, deficiency of Nlrp6 in mice aggravates the severity of nephrotoxic acute kidney injury, characterized by enhanced apoptotic and pro‐inflammatory responses in the tubular cells, suggesting a nephroprotective role of NLRP6 in acute kidney injury 62 . Taken together, the complicated and multifaceted functions of NLRP6 in regulating disease associated with a multitude of organs warrant a continued thorough investigation.…”

Tacrolimus Prevents TWEAK-Induced PLA2R Expression in Cultured Human Podocytes

“…Blots were washed with PBS/Tween and subsequently incubated with appropriate horseradish peroxidase-conjugated secondary antibody (1:2000, Amersham, Aylesbury, UK). After washing, blots were developed with the chemiluminescence method (ECL, Amersham, UK), and then probed with the mouse monoclonal anti-α-tubulin antibody (1:5000, Sigma, St, Louis, MO, USA) [32]. Levels of expression were corrected for minor differences in loading.…”