Abstract
Ras homolog enriched in brain (Rheb1), a small GTPase, plays a crucial role in regulating cell growth, differentiation, and survival. However, the role and mechanisms for Rheb1 in tubular cell survival and acute kidney injury (AKI) remain unexplored. Here we found that Rheb1 signaling was activated in kidney tubule of AKI patients and cisplatin-treated mice. A mouse model of tubule-specific deletion of Rheb1 (Tubule-Rheb1−/−) was generated. Compared to control littermates, Tubule-Rheb1−/− mice were phenotypically normal within 2 months after birth but developed more severe kidney dysfunction, tubular cell death including apoptosis, necroptosis and ferroptosis, mitochondrial defect and less PGC-1α expression after cisplatin injection. In primary cultured tubular cells, Rheb1 ablation exacerbated cisplatin-induced cell death and mitochondrial defect. Furthermore, haploinsufficiency for Tsc1 in tubular cells led to Rheb1 activation and mitigated cisplatin-induced cell death, mitochondrial defect and AKI. Together, this study uncovers that Rheb1 may protect against cisplatin-induced tubular cell death and AKI through maintaining mitochondrial homeostasis.
Highlights
Acute kidney injury (AKI), a clinical syndrome characterized by an abrupt loss of kidney function within hours, is a worldwide health problem with high mortality[1]
Our results demonstrate that tubular Ras homolog enriched in brain (Rheb)[1] protects against tubular cell death and AKI through maintaining mitochondrial homeostasis
The results showed that weak Rheb[1] and little p-S6 were detected in control kidney tissues, while in kidney tubule of AKI patients, both Rheb[1] and p-S6 abundance was significantly increased (Fig. 1a–c)
Summary
Acute kidney injury (AKI), a clinical syndrome characterized by an abrupt loss of kidney function within hours, is a worldwide health problem with high mortality[1]. Tremendous effort has been made by the nephrologist during the past decades, the therapeutic strategy for AKI patients is mainly supportive in nature up to date[2]. Deciphering the underlying mechanisms of AKI and pursuing efficient strategy for preventing and treating AKI in patients is necessary. The pathogenic factors for AKI in patients are mainly comprised by ischemia, renal toxic reagents, and sepsis[3]. The products of Rheb[1] and Rheb[2] genes share 54% identity and 74% similarity. Rheb[1] is ubiquitously expressed while Rheb[2] is mainly expressed in brain[10].
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