Abstract
Diabetic kidney disease (DKD) is the most common cause of severe renal disease worldwide and the single strongest predictor of mortality in diabetes patients. Kidney steatosis has emerged as a critical trigger in the pathogenesis of DKD; however, the molecular mechanism of renal lipotoxicity remains largely unknown. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase 25 (STK25) as a critical regulator of ectopic lipid storage in several metabolic organs prone to diabetic damage. Here, we demonstrate that overexpression of STK25 aggravates renal lipid accumulation and exacerbates structural and functional kidney injury in a mouse model of DKD. Reciprocally, inhibiting STK25 signaling in mice ameliorates diet-induced renal steatosis and alleviates the development of DKD-associated pathologies. Furthermore, we find that STK25 silencing in human kidney cells protects against lipid deposition, as well as oxidative and endoplasmic reticulum stress. Together, our results suggest that STK25 regulates a critical node governing susceptibility to renal lipotoxicity and that STK25 antagonism could mitigate DKD progression.
Highlights
Diabetic kidney disease (DKD) occurs in almost one-third of diabetes patients and is one of the most fatal long-term diabetic complications [1]
We found that the staining with MitoTracker Red, a fluorescent dye that accumulates within respiring mitochondria, was significantly augmented in oleate-treated human embryonic kidney 293 (HEK293) cells transfected with serine/threonine protein kinase 25 (STK25) small interfering RNA (siRNA) versus nontargeting control (NTC) siRNA (Figure 7F)
We found that overexpression of STK25 in mice challenged with a high-fat diet triggered DKD-associated pathologies, including exacerbated glomerular mesangial matrix expansion, glomerular basement membrane (GBM) thickening, and impairment in the integrity of glomerular filtration barrier (GFB), vacuolar degeneration of tubular cells and interstitial edema, worsened glomerulosclerosis and tubulointerstitial fibrosis, aggravated renal arteriolar hyalinosis, and elevated albuminuria (Figure 9)
Summary
Diabetic kidney disease (DKD) occurs in almost one-third of diabetes patients and is one of the most fatal long-term diabetic complications [1]. DKD is the most common cause of end-stage renal disease (ESRD) in the Western world, accounting for nearly 40% of newly diagnosed cases that require dialysis or kidney transplantation [1], its molecular pathogenesis remains incompletely understood. Disease mechanisms other than hyperglycemia may be more relevant in DKD [3]. Kidney lipotoxicity (i.e., lipid accumulation in glomerular and tubular cells) has emerged as a critical trigger in the pathogenesis of DKD through induction of renal oxidative stress, chronic low-grade inflammation, and extracellular matrix deposition [4,5,6,7,8].
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