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 ß-synthase (CBS), cystathionine ¿-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.