Human tissue kallikrein 1 ameliorates erectile function via modulation of macroautophagy in aged transgenic rats

Abstract

Previously, we have demonstrated that human tissue kallikrein 1 (hKLK1) improves age-related erectile dysfunction (ED). Autophagy has been implicated in age-related diseases, including ED. However, the molecular mechanisms underlying hKLK1-mediated amelioration of age-related ED via regulation of autophagy remains unknown. To explore the potential mechanism, male wild-type Sprague-Dawley rats (WTR) and transgenic rats harboring human KLK1 (TGR) were bred till 4 or 18 months of age and divided into three groups: young WTR (yWTR) as the control group, aged WTR (aWTR) group, and aged TGR (aTGR) group. The erectile function of each rat was evaluated using cavernous nerve electrostimulation. The ratio of intracavernous pressure/mean arterial pressure (ICP/MAP) and total ICP were also measured. Western blotting, immunohistochemistry, and transmission electron microscopy were performed to detect the levels of autophagy. The expression levels of related signaling pathways were determined by western blotting and immunohistochemistry. We found that hKLK1 improved the impaired erectile function of aged rats. Compared to the yWTR and aTGR groups, the aWTR group showed reduced smooth muscle/collagen ratio, fewer autophagosomes, and lower expression of Beclin 1 and LC3-II, which indicate impaired smooth muscle function and low level of autophagy in the smooth muscle cells. Moreover, the PI3K/Akt/mTOR signaling pathway, which is considered to be a negative regulator of autophagy, was upregulated in the aWTR group. hKLK1 may partially restore erectile function in aged transgenic rats by upregulating protective autophagy via the PI3K/Akt/mTOR pathway. These observations indicate that hKLK1 is a potential gene therapy candidate for age-related ED.

Restoration of erectile function by suppression of corporal apoptosis and oxidative stress with losartan in aged rats with erectile dysfunction

“…29,30 Factors leading to ED may result from impaired erection or the disruption of normal penile components. 31 Aging has been recog- injury 18 and Nrf2/Keap-1 pathway has been reported to play an important role in the mechanism against oxidative damage. 19 These two pathways were also reconfirmed their role in AED.…”

Simvastatin alleviated diabetes mellitus‐induced erectile dysfunction in rats by enhancing AMPK pathway‐induced autophagy

“…Autophagy is a programmed process in which the cell swallows and degrades the cytoplasmic contents to supplement metabolic needs . Previous studies showed that enhanced autophagy could alleviate the fibrosis process of the corpus cavernosum and thus improve erectile function . In this study, autophagy in the corpus cavernosum was enhanced in DMED rats, which might be because of the compensatory autophagy enhancement to clear the damaged cell structures.…”

Enhanced effects of salidroside on erectile function and corpora cavernosa autophagy in a cavernous nerve injury rat model

“…Autophagy is a self‐regulating mechanism for cells to obtain nutrients needed to maintain survival and is also an important self‐regulating system for cells to inhibit apoptosis and fibrosis. Previous studies have reported the autophagic change in the CC associated with ageing, hyperlipidaemia and diabetes‐induced ED (Li, Cui, et al., 2017; Tang et al., 2018; Zhang et al., 2019). However, to our knowledge, this is the first report of autophagy in the CC of a rat with BCNI.…”