Renal Inflammation and Innate Immune Activation Underlie the Transition From Gentamicin-Induced Acute Kidney Injury to Renal Fibrosis

Abstract

Subjects recovering from acute kidney injury (AKI) are at risk of developing chronic kidney disease (CKD). The mechanisms underlying this transition are unclear and may involve sustained activation of renal innate immunity, with resulting renal inflammation and fibrosis. We investigated whether the NF-κB system and/or the NLRP3 inflammasome pathway remain activated after the resolution of AKI induced by gentamicin (GT) treatment, thus favoring the development of CKD. Male Munich-Wistar rats received daily subcutaneous injections of GT, 80 mg/kg, for 9 days. Control rats received vehicle only (NC). Rats were studied at 1, 30, and 180 days after GT treatment was ceased. On Day 1, glomerular ischemia (ISCH), tubular necrosis, albuminuria, creatinine retention, and tubular dysfunction were noted, in association with prominent renal infiltration by macrophages and myofibroblasts, along with increased renal abundance of TLR4, IL-6, and IL1β. Regression of functional and structural changes occurred on Day 30. However, the renal content of IL-1β was still elevated at this time, while the local renin-angiotensin system remained activated, and interstitial fibrosis became evident. On Day 180, recurring albuminuria and mild glomerulosclerosis were seen, along with ISCH and unabated interstitial fibrosis, whereas macrophage infiltration was still evident. GT-induced AKI activates innate immunity and promotes renal inflammation. Persistence of these abnormalities provides a plausible explanation for the transition of AKI to CKD observed in a growing number of patients.

Understanding the Renal Fibrotic Process in Leptospirosis

“…The transition of acute kidney injury (AKI) caused by leptospiral infection to chronic infection and, consequently, kidney fibrosis is still not completely understood, and many research gaps remain open. This is also applied to the transition from AKI to CKD of non-infectious cause [ 149 ]. Continuous stimuli, the activation of inflammatory pathways, and the participation of innate immune cells in the development of chronic leptospirosis and kidney fibrosis are the main underlying causes that have been considered so far [ 25 , 142 , 143 , 149 , 150 , 151 ].…”

“…This is also applied to the transition from AKI to CKD of non-infectious cause [ 149 ]. Continuous stimuli, the activation of inflammatory pathways, and the participation of innate immune cells in the development of chronic leptospirosis and kidney fibrosis are the main underlying causes that have been considered so far [ 25 , 142 , 143 , 149 , 150 , 151 ].…”

“…One month after infection, cellular infiltration in the kidneys is characterized by CD3-positive T-cells and CD11b-positive macrophages/monocytes, but no more neutrophils are observed [ 152 ]. In a rat model of gentamicin-induced acute kidney injury, the most prevalent cell infiltrate in kidneys were pro-inflammatory M1 macrophages within the first day after injury; whereas, at day 30 after injury, M2 macrophages accounted for 45% of the total cell infiltrate [ 149 ].…”

“…Activation of the NF-κB and NLRP3/IL-1β pathways are implicated in the recrudescence of signs in rat kidneys 180 days after injury, with a low-grade inflammation occurring together with activation of Angiotensin II, as well as collagen and fibronectin deposition in the interstitium. These findings indicate that sustained inflammatory stimulus may lead to kidney fibrosis after acute injury [ 149 ].…”

“…In brief, acute leptospirosis is characterized mainly by inflammatory and immune responses mediated by cells, but it triggers the initial activation of the above-mentioned pathways, such as TGF-β1 and Wnt/β-catenin. Their sustained and imbalanced activation will then promote major effects on the occurrence of EMT and kidney fibrosis during infection [ 25 , 132 , 149 ].…”