Regulated cell death pathways in kidney disease

Abstract

Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to the pathogenesis of kidney disease. Acute kidney injury can result from an acute loss of kidney epithelial cells. In chronic kidney disease, loss of kidney epithelial cells leads to glomerulosclerosis and tubular atrophy, whereas interstitial inflammation and fibrosis result from an excess of leukocytes and myofibroblasts. Other conditions, such as acquired cystic disease and kidney cancer, are characterized by excess numbers of cyst wall and malignant cells, respectively. Cell death modalities act to clear unwanted cells, but disproportionate responses can contribute to the detrimental loss of kidney cells. Indeed, pathways of regulated cell death — including apoptosis and necrosis — have emerged as central events in the pathogenesis of various kidney diseases that may be amenable to therapeutic intervention. Modes of regulated necrosis, such as ferroptosis, necroptosis and pyroptosis may cause kidney injury directly or through the recruitment of immune cells and stimulation of inflammatory responses. Importantly, multiple layers of interconnections exist between different modalities of regulated cell death, including shared triggers, molecular components and protective mechanisms.

Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced AKI

“…To explore which cell death pathways were upregulated in the mouse kidney tissues, we ran Western blots of total kidney protein lysates from treated mice and probed with known biomarkers of cell death mechanisms that occur in cisplatininduced AKI. 27,28 The markers tested included: for apoptosis detection-cleaved caspase-3; for necroptosis-receptor interacting protein kinases-1 (RIPK1), receptor interacting protein kinases-3 (RIPK3), and total and pMLKL proteins; and for pyroptosis detection-cleaved GSDME-N. Interestingly, the results show that RIPK1, RIPK3, total MLKL, and GSDME-N cleaved proteins were upregulated in cisplatin alone treated mouse kidneys, and on cotreatments with AZD5438 or dabrafenib, the levels of these markers were significantly reduced (Figure 7, A-G). AZD5438 cotreatment restored the levels of GSDME-full length (FL), total MLKL, RIPK1, and RIPK3 to the levels of carrier alone treated mice and inhibited the cleavage of GSDME-FL to the cleaved form GSDME-N. Dabrafenib restored the levels of total MLKL, inhibited cleavage of GSDME-FL, and significantly reduced RIPK1 and RIPK3 levels (Figure 7, A-G, and Supplemental Figures 6 and 7).…”

“…Cisplatin has been shown in both tissue types to cause DNA damage, mitochondrial injury, production of reactive oxygen species, triggering of inflammatory responses, and cell death signaling pathways, including pyroptosis and necroptosis. 27,28 The kidney and inner ear cells share similar transport proteins, such as ATP6V1B1 and ATP6V0A4, which can contribute to relatable pharmacologic activity of drugs in the two organs. [24][25][26]29,30 Herbal Chinese medicine points to similarities between drugs that work in the kidney and ear tissues.…”

Renal-Protective Roles of Lipoic Acid in Kidney Disease

“…CKD occurs when there’s a gradual decline in renal function for more than 3 months due to damage to glomerular filtration and tubular injuries [ 7 ]. It has been projected that by 2040, CKD will become the fifth leading cause of death worldwide [ 8 ]. On the other hand, AKI occurs when there’s a rapid decline in renal function for less than 3 months, and this is indicated by acidosis, fluid overload, and abnormalities with electrolytes and hematology changes [ 7 ].…”

“…On the other hand, AKI occurs when there’s a rapid decline in renal function for less than 3 months, and this is indicated by acidosis, fluid overload, and abnormalities with electrolytes and hematology changes [ 7 ]. It is also known that individuals with CKD can have an increased risk of AKI [ 8 ]. Currently, there are no pharmaceutical products to cure AKI or CKD.…”

“…Nutrients 2023, 15, x FOR PEER REVIEW 2 of 18 overload, and abnormalities with electrolytes and hematology changes [7]. It is also known that individuals with CKD can have an increased risk of AKI [8]. Currently, there are no pharmaceutical products to cure AKI or CKD.…”