We aimed to investigate the role of renal pericyte pyruvate kinase M2 (PKM2) in the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). The role of PKM2 in renal pericyte‐myofibroblast transdifferentiation was investigated in an AKI‐CKD mouse model. Platelet growth factor receptor beta (PDGFRβ)‐iCreERT2; tdTomato mice were used for renal pericyte tracing. Western blotting and immunofluorescence staining were used to examine protein expression. An 5‐ethynyl‐2′‐deoxyuridine assay was used to measure renal pericyte proliferation. A scratch cell migration assay was used to analyse cell migration. Seahorse experiments were used to examine glycolytic rates. Enzyme‐linked immunoassay was used to measure pyruvate kinase enzymatic activity and lactate concentrations. The PKM2 nuclear translocation inhibitors Shikonin and TEPP‐46 were used to alter pericyte transdifferentiation. In AKI‐CKD, renal pericytes proliferated and transdifferentiated into myofibroblasts and PKM2 is highly expressed in renal pericytes. Shikonin and TEPP‐46 inhibited pericyte proliferation, migration, and pericyte‐myofibroblast transdifferentiation by reducing nuclear PKM2 entry. In the nucleus, PKM2 promoted downstream lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1) transcription, which are critical for glycolysis. Therefore, PKM2 regulates pericyte glycolytic and lactate production, which regulates renal pericyte‐myofibroblast transdifferentiation. PKM2‐regulated renal pericyte‐myofibroblast transdifferentiation by regulating downstream LDHA and GLUT1 transcription and lactate production. Reducing nuclear PKM2 import can reduce renal pericytes‐myofibroblasts transdifferentiation, providing new ideas for AKI‐CKD treatment.

Objectives: Ischemia–reperfusion injury (IRI) is a major cause of chronic renal fibrosis. Currently, numerous therapies have shown a minimal effect on the blockade of fibrosis progression. Here, the therapeutic potential of peptide‐based TGF‐β1 inhibitor P144 in IRI‐induced renal fibrosis and the underlying mechanism were analyzed.Materials and Methods: The unilateral ischemia–reperfusion injury with the contralateral nephrectomy model was established, and the P144 was administered intravenously 1d/14d after the onset of IRI. The histopathology and immunofluorescence staining were used to detect renal fibrosis and macrophage infiltration. The in vivo fluorescence imaging was used to measure the bio‐distribution of P144. The transwell assays were used to observe the migration of macrophages. RT‐qPCR and western blot were used to analyze TGF‐β1 signaling.Results: P144 ameliorated the accumulation of extracellular matrix in the kidney and improved the renal function in the unilateral ischemia–reperfusion injury plus contralateral nephrectomy model. Mechanistically, P144 downregulated the TGF‐β1‐Smad3 signaling at both the transcriptional and translational levels and further reduced the TGF‐β1‐dependent infiltration of macrophages to the injured kidney. Additionally, P144 blocked the polarization of macrophages to an M2‐like phenotype induced by TGF‐β1 in vitro, but showed no effect on their proliferation.Conclusions: Our study showed that the TGF‐β1 peptide‐based inhibitor P144 decreased renal fibrosis through the blockade of the TGF‐β1–Smad3 signaling pathway and the modulation of macrophage polarization, suggesting its potential therapeutic use in IRI‐induced renal fibrosis.

The presence of macrophages surrounding lipotoxic tubular epithelial cells (TECs) is a hallmark of diabetic nephropathy (DN). Nevertheless, the mechanisms of communication between these cell types are not well understood. Previous studies have revealed a unique subset of macrophages that express triggering receptor expressed on myeloid cells 2 (Trem2) in kidneys of human patients and mice with DN. Here, we explored the characteristics and the function of Trem2+ macrophages in the progress of DN. RNA-sequencing of macrophages in kidneys of Trem2 knockout (KO) mice fed a high-fat diet plus streptozotocin (HFD/STZ) revealed functional enrichment of metabolic processes, cytokine production, positive regulation of extracellular signal-regulated kinase (ERK) cascades, and the regulation of phagocytosis. In vivo studies demonstrated that Trem2+ macrophages reduced lipid accumulation and mitigated ferroptosis of TECs in diabetic mice. Mechanistically, Trem2-deficient macrophages amplified the production of interleukin-1β (IL-1β) through activating the ERK signaling pathway. Furthermore, IL-1β triggered CD36 expression via the transcription factor NF-κB. Bioinformatics and functional assays showed NF-κB binds the CD36 promoter, which directly bound to the promoters of CD36 to facilitate its transcription. Inhibition of NF-κB blocked IL-1β–induced CD36 production. This mechanism is exacerbated in Trem2-deficient macrophages, which release excess IL-1β to activate NF-κB in tubular cells, promoting CD36-dependent lipid uptake and ferroptosis. Additionally, we found Trem2 plays a role in enhancing the phagocytosis and clearance of ferroptotic cells by bone marrow-derived macrophages. Altogether, our results suggest Trem2+ macrophages maintain homeostasis of the renal microenvironment and exert a protective function in DN. Article Highlights: Levels of triggering receptor expressed on myeloid cells 2 (Trem2) in macrophages are increased in human patients and in mice with diabetic nephropathy. Trem2 suppresses the extracellular signal-regulated kinase signaling pathways, thereby inhibiting IL-1β production in macrophages. Macrophage Trem2 deficiency exacerbates tubular cell lipid deposition and ferroptosis by increasing CD36 expression in an IL-1β–dependent manner

Objective: The Global Burden of Disease Study (GBD) 2019 reveals an increasing prevalence of diabetic nephropathy caused by excessive intake of sugar-sweetened beverages in high and low SDI regions from 1990 to 2021.Methods: This study comprehensively analyzed the burden of DN caused by SSBs in high and low SDI regions from 1990 to 2021 and projected the trends until 2040 using ARIMA models.Results: The results revealed distinct patterns and trends in age-standardized rates of deaths, DALYs, YLDs, and YLLs between the two regions. In high SDI regions, the age-standardized rates of deaths, DALYs, YLDs, and YLLs exhibited a consistent upward trend from 1990 (0.044, 1.425, 0.537, 0.888 per 100,000) to 2021 (0.096, 2.284, 0.67, 2.154 per 100,000). Projections for the age-standardized rates in high SDI regions from 2021 to 2040 indicate that these upward trends will persist, with deaths, DALYs, YLDs, and YLLs further increasing to 0.127, 3.629, 1.070, and 2.861 per 100,000. Conversely, low SDI regions displayed different trends. Although the age-standardized rates of deaths, DALYs, YLDs, and YLLs also increased from 1990 (0.018, 0.488, 0.071, 0.417 per 100,000) to 2021 (0.020, 0.522, 0.081, 0.441 per 100,000), the rate of increase was relatively slower compared to high SDI regions. Projections for the age-standardized rates in low SDI regions from 2021 to 2040 suggest that these upward trends will continue, with deaths, DALYs, YLDs, and YLLs further increasing to 0.016, 0.498, 0.105, and 0.398 per 100,000.Conclusion: This study provides a comprehensive analysis of the burden of type 2 diabetes nephropathy caused by excessive intake of sugar-sweetened beverages in high and low SDI regions. The results revealed distinct patterns and trends in age-standardized rates of deaths, DALYs, YLDs, and YLLs between the two regions.