miRNA Mechanism of Acute Kidney Injury in Aging

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Project Summary Ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) remains a major clinical problem in older population. Although I/R-induced AKI occurs in a variety of clinical situations such as shock, renal transplantation, sepsis and renal artery stenosis, the mechanism is multifactorial, complex and poorly understood. Under normal physiological conditions, kidney produces hydrogen sulfide (H2S) with the aid of four enzymes: cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3MST), and cysteine aminotransferase (CAT). In recent years, H2S has been shown to regulate several physiological functions, and its decrease has been implicated in diseases such as hypertension, inflammation, atherosclerosis, and renal disease progression and failure. MicroRNA’s (miRNAs) are small non-coding RNA’s, which has the ability to inhibit mRNA transcripts by inducing degradation or blocking protein translation. In I/R- induced AKI, several miRNAs have been reported to be differentially expressed. Furthermore, in I/R-induced AKI macrophages play a key role in inflammatory and reparative process. While M1 subset macrophage is involved in inflammation, subset M2 is involved in repair mechanism. Our preliminary results suggested that in I/R-induced AKI in aging miRNA-21 is upregulated and miRNA-194 is down regulated. The injured kidney also showed decreased expression of CBS and 3MST enzymes leading to diminished H2S production. The increased ratio of M1/M2 further suggested prolonged inflammatory phase. In addition, expression of matrix metalloproteinase-9 (MMP-9) and their regulatory molecules, EMMPRIN and Meprin-A were also upregulated in AKI. These changes in concert with endothelial to mesenchymal transition (EndoMT) led us to strongly believing a detrimental remodeling in I/R-induced old kidney. Interestingly, H2S treatment mitigated remodeling and improved renal function in I/R-induced AKI in old mice. We obtained similar results through miR-21 inhibitor treatments. Based on these preliminary findings, we hypothesize that H2S is a protective agent against I/R-induced damage in aging kidney. In further substantiating our concept, both male and female, old vs young wild type (WT, C57BL/6J) mice will be used to compare severity of I/R-induced kidney injury and dysfunction, and beneficial effects of H2S treatment will be assessed. The gained knowledge will not only help to better understand mechanisms of AKI in aging, but will also shed lights on future diagnostic and therapeutic strategies which will be applicable to older patients suffering from AKI.